Steroid total synthesis process utilizing a cyanoalkyl A-ring precursor

ABSTRACT

A multi-step, stereospecific total synthesis of steroids utilizing intermediates having a cyanoalkyl A-ring precursor is disclosed. The initial starting materials for this process are the relatively inexpensive and commercially available reagents γ-butyrolactone and sodium cyanide. The process is suitable for the preparation of racemic or optically active, medicinally valuable steroids, particularly 19-norsteroids. It is a feature of this process that conditions employed during the multiple step synthesis are selected so as to retain the normally labile nitrile group even during hydrogenation and hydrolysis steps. In this manner, it is possible to employ the nitrile group as an A-ring precursor without resorting to protective groups as was heretofore found necessary in previous steroid total synthesis processes.

This is a division of application Ser. No. 642,817, filed Dec. 22, 1975,now U.S. Pat. No. 4,045,452, which is a division of application Ser. No.450,701 filed Mar. 13, 1974, now U.S. Pat. No. 3,991,084, which is adivision of application Ser. No. 67,296 filed Aug. 26, 1970, now U.S.Pat. No. 3,813,417 issued May 28, 1974.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to a multi-step, stereospecific totalsynthesis of racemic or optically active, medicinally valuable steroidsutilizing a cyanoalkyl A-ring precursor. This synthesis is particularlyadapted to produce 19-norsteroids.

One aspect of the present invention involves the preparation of racemicor optically active compounds of the following formula: ##STR1## whereinR₁ is a primary alkyl group of from 1 to 5 carbon atoms; R₂ is hydrogen,lower primary alkyl or acyl; Z is carbonyl or a group of the formula##STR2## where R₇ is hydrogen, lower acyl, lower alkyl, aryl lower alkylor tetrahydropyran-2-yl; R₈ is hydrogen or lower aliphatic hydrocarbyl;T is either a single or double bond, U is a single or double bond and isa single bond when T is a single bond; m is 1 or 2; n is 0 or 1 and is 0when T is a double bond and is 1 when T is a single bond; r is 0 or 1and is 0 when T is a double bond and 1 when T is a single bond; and S is0 or 1 and is 0 when U is a double bond and 1 when U is a single bond.

As used throughout the specification and appended claims, the term"hydrocarbyl group" denotes a monovalent substituent consisting solelyof carbon and hydrogen and having from 1 to 20 carbon atoms; the term"aliphatic" with reference to hydrocarbyl groups, denotes groupscontaining no aromatic unsaturation, but which can be saturated orunsaturated, i.e., an alkyl, alkenyl or alkynyl group; the term "alkylgroup" denotes a saturated hydrocarbyl group with a straight or branchedor branched chain having 1 to 20 carbon atoms; the term "alkenyl"denotes a straight or branched chain hydrocarbyl group having at leastone olefinic bond and containing from 1 to 20 carbon atoms; the term"alkynyl group" denotes a straight or branched chain hydrocarbyl groupcontaining at least one acetylenic bond having from 1 to 20 carbonatoms; the term "primary alkyl group" denotes an alkyl group having itsvalence from a carbon bonded to at least two hydrogens; the term "acylgroup" denotes a group consisting of the residue of a hydrocarbylmonocarboxylic acid having 1 to 18 carbon atoms formed by removal of thehydroxyl portion of the carboxyl group; and the term "lower", as appliedto any of the foregoing groups, denotes a group having a carbon skeletoncontaining up to and including 8 carbon atoms, such as methyl, ethyl,butyl, tertiary butyl, hexyl, 2-ethylhexyl, vinyl butenyl, hexenyl,ethynyl, ethylene, methylene, formyl, acetyl, 2-phenylethyl, and thelike.

In the formulae presented herein, the various substituents on cycliccompounds are joined to the cyclic nucleus by one of three notations, asolid line (--) indicating a substituent which is in the β-orientation,(i.e., above the plane of the paper), a dotted line (---) indicating asubstituent which is in the α-orientation (below the plane of the paper)or a wavy line ( ) indicating a substituent which may be either the α-or β-orientation. The position of R₁ has been arbitrarily indicated asthe β-orientation, although the products obtained in the examples areall racemic compounds unless otherwise specified.

Preferred compounds are those wherein R₁ is n-alkyl, especially methyland ethyl; m is 1 and, when s has a value of 1, the 9a-(when m is 1) or10a- (when m is 2) hydrogen is trans-oriented with respect to R₁.

Subgeneric to the tricyclic compounds of formula I are the "dienes"having the formula: ##STR3## where R₁, m and Z are as above;

The "monoenes", represented by the formula ##STR4## where R₁, m and Zare as above; and

The "perhydro" compounds represented by the formula: ##STR5## where R₁,R₂, m and Z are as above.

A further aspect of the present invention relates to processes useful inthe preparation of compounds of formula Ia, utilizing commerciallyavailable and relatively inexpensive starting materials. For example, apreferred synthesis route for the preparation of compounds of formulaIa, utilizes 2,2-di-(3-cyanopropyl)-1,3-dioxolane as starting material.The latter compound is a known chemical which may be prepared in amanner known per se from δ-butyrolactone utilizing sodium cyanide as thesource of the cyano groups. It is within the scope of the processes ofthe present invention to prepare either racemic or optically activeforms of compounds of formula Ia. Such processes are summarized in thefollowing reaction scheme: ##STR6##

    __________________________________________________________________________    CHART FOR REACTION SCHEME I                                                   Reagents               Solvent           Conditions                           Step                                                                             Operable    Preferred                                                                             Operable    Preferred                                                                           Operable                                                                            Preferred                                                                           Remarks                  __________________________________________________________________________    A  dilute aqueous mineral                                                                    dilute aqueous                                                                        a water miscible or-                                                                      acetone                                                                             -20 to                                                                              10 to 30°                  acid; e.g., hydro-                                                                        hydrochloric                                                                          ganic solvent selected                                                                          +50°                             chloric acid; dilute                                                                      acid    from the group con-                                       aqueous organic acid,                                                                             sisting of ketones,                                       e.g., acetic acid   e.g., acetone; ethers,                                                        e.g., tetrahydrofuran                                                         and organic acids, e.                                                         g., acetic acid                                        B  alkali metal borohy-                                                                      sodium  a non-ketonic organic                                                                     aqueous                                                                             -20° to                                                                      10° to 30°          drides, e.g., sodium                                                                      borohydride                                                                           solvent selected from                                                                     methanol                                                                            boiling                                 borohydride; alkoxy the group consisting                                                                            point of                                substituted alkali  of lower alkanols,                                                                              solvent                                 metal borohydrides, e.                                                                            e.g., methanol; water                                     g., trimethoxysodium                                                                              miscible ethers, e.g.,                                    borohydride; alkoxy tetrahydrofuran;                                          substituted complex pyridine and dimethyl-                                    metal hydride, e.g.,                                                                              formamide; or a mix-                                      lithium aluminum tri-                                                                             ture of water and one                                     t-butoxy hydride.   or more of the above.                                  C  one equivalent each of                                                                    one equivalent                                                                        hydrocarbons, e.g.                                                                        toluene                                                                             20° to                                                                       80° to                     water and an acid                                                                         of p-toluene-                                                                         toluene, ethers, e.g.                                                                           150°                                                                         120°                       selected from the group                                                                   sulfonic acid                                                                         tetrahydrofuran;                                          consisting of mineral                                                                     monohydrate                                                                           dimethylformamide.                                        acids, e.g. sulfuric                                                                      or one                                                            acid, and organic                                                                         equivalent                                                        sulfonic acids, e.g.                                                                      each of water                                                     p-toluenesulfonic acid                                                                    and sulfuric                                                                  acid.                                                          D  vinyl magnesium                                                                           vinyl   ethers, e.g. diethyl                                                                      tetrahydro-                                                                         -20°                                                                         -40° to                                                                      Product VI is not           halides, e.g. vinyl                                                                       magnesium                                                                             ether, tetrahydrofuran                                                                    furan to    -70°                                                                         isolated.                   magnesium chloride;                                                                       chloride                  -100°                            vinyl alkali metals,                                                          e.g., vinyl lithium                                                        E  hydrohalic acids, e.g.                                                                    for racemic                                                                           where solubility                                                                          tetrahydro-                                                                         0° to 50°                                                             10° to 30°          hydrochloric acid;                                                                        series -                                                                              permits, the reagent                                                                      furan                                         lower alkanols, e.g.                                                                      diethylamine;                                                                         employed, e.g.                                            methanol; water; mono                                                                     for optically                                                                         methanol; hydro-                                          lower hydrocarbyl                                                                         active series                                                                         carbons, e.g. benzene;                                    amines, e.g. α-methyl-                                                              d- or l-α-                                                                      ethers, e.g. tetra-                                       benzylamine; di(lower                                                                     methylbenzyl-                                                                         hydrofuran.                                               hydrocarbyl)amines.                                                                       amine.                                                            e.g. diethylamine.                                                         F  2-alkylcyclopentan-                                                                       2-methylcyclo-                                                                        hydrocarbons, e.g.                                                                        toluene                                                                             20° to 150°                                                           80° to                                                                       An acidic or basic          1,3-diones; 2-alkyl-                                                                      pentan-1,3-                                                                           toluene; ethers, e.g.         catalyst can be             cyclohexan-1,3-diones.                                                                    dione; 2-                                                                             tetrahydrofuran;              used, preferably                        ethylcyclo-                                                                           dimethylformamide;            a lower alkanoic                        pentan-1,3-                                                                           dimethylsulfoxide.            acid, e.g. acetic                       dione                                 acid.                    G  a non-optically active                                                                    oxalic acid                                                                           ketones e.g. acetone;                                                                     acetone,                                                                            -10° to                                                                      20° to 80°          acid selected from the                                                                            lower alkanols, e.g.                                                                      aceto-                                                                              120°                             group consisting of methanol; ethers, e.g.                                                                    nitrile                                       mineral acids, e.g. diethyl ether; hydro-                                     hydrochloric acid;  carbons, e.g. benzene;                                    hydrocarbylmonocarbox-                                                                            nitriles, e.g. aceto-                                     ylic acids, e.g. acetic                                                                           nitrile.                                                  acid, hydrocarbyl                                                             dicarboxylic acids,                                                           e.g. oxalic acid.                                                          H  a. water; lower alkan-                                                                    a. methanol                                                                           lower alkanols, e.g.                                                                      methanol                                                                            20° to 120°                                                           40° to                                                                       a catalytic amount          ols, e.g. methanol; methanol; hydrocarbons        of an inorganic             b. lower hydrocarbyl                                                                      b. benzalde-                                                                          e.g. toluene; ethers,         base, preferably            or aromatic aldehydes,                                                                    hyde    e.g. tetrahydrofuran.         alkali metal car-           e.g. benzaldehyde.                                ate, e.g. sodium                                                              bicarbonate may                                                               be employed.             I  2-alkylcyclopentan-                                                                       2-methylcyclo-                                                                        hydrocarbons, e.g.                                                                        toluene                                                                             20° to 150°                                                           80° 120°                                                              an acidic or basic          1,3-diones; 2-alkyl-                                                                      pentan-1,3-                                                                           toluene; ethers, e.g.         catalyst can be             cyclohexan-1,3-diones.                                                                    dione; 2-                                                                             tetrahydrofuran;              used, preferably                        ethylcyclo-                                                                           dimethylformamide;            a lower alkanoic                        pentan-1,3-                                                                           dimethylsulfoxide.            acid, e.g. acetic                       dione.                                acid.                    __________________________________________________________________________

In step A the known compound 2,2-di(3-cyanopropyl)-1,3-dioxolane wasselectively hydrolyzed utilizing dilute aqueous acid in the presence ofa water-miscible organic solvent to yield 5-oxoazeleonitrile (III).Conditions for this hydrolysis are selected so as to retain the normallylabile nitrile groups. Reduction of the carbonyl function in compoundIII is accomplished in Step B utilizing a metal hydride reducing agent,e.g., sodium borohydride to produce 5-hydroxyazeleonitrile (IV).

The symmetrical di-cyano alcohol produced above (IV) is then subjectedto a selective acid hydrolysis procedure in Step C so as to produce8-cyano-5-hydroxy-octanoic acid lactone. For this reaction it isnecessary to employ one equivalent of water and one equivalent of strongacid, such as a mineral acid or an organic sulfonic acid such asp-toluene sulfonic acid. By utilizing one equivalent each of thesereagents, it is possible to selectively hydrolyze only one of the twoequivalent cyano moieties in compound IV.

It is likely that this reaction proceeds through the intermediate##STR7## which is hydrolyzed by the water present to V.

In Step D the lactone of formula V is treated with a vinylating agentsuch as vinyl Grignard to produce a tautomeric mixture of6-(3-cyanopropyl)-2-vinyl-tetrahydropyran-2-ol (which is named as amatter of convenience as a closed form). This reaction is highlyselective in that the reactive nitrile group is not affected by thevinylating agent under the carefully controlled reaction conditions.

Because of the susceptibility of the vinyl group of the compound offormula VI to polymerization, it is highly desirable to convert thiscompound without isolation to a more stable variant in Step E so as toproduce a compound of formula VII. This is accomplished by treating thecompound of formula VI with either water, an indicated hydrogen halide,a lower alkanol or a primary or secondary amine.

When it is desired to ultimately produce a racemic compound from thisprocess scheme, it is possible to utilize any of the aforementionedreactants in process Step E, although a reactant of greatest preferenceis a di(lower hydrocarbyl)amine, preferably a di(lower alkyl)amine suchas diethyl amine. In a final process step for the production of aracemic compound of formula Ia', the compound of formula VII is reactedin process Step F with a 2-alkyl-cyclopentan-1,3-dione or a2-alkyl-cyclohexan-1,3-dione.

Where it is desirable to produce optically active benzopyrans, it isnecessary to employ in Step E an optically active primary or secondaryamine so as to produce a compound of formula VII which is substitutedwith such an optically active amino group. Suitable optically activeamines for this purpose include α-methyl-benzylamine (also known asα-phenethylamine), dehydro-abiethylamine or desoxyephedrine.

When compound VIII contains an optically active amino moiety as R₁₆, itcan be conveniently resolved in Step G to compound VIII. This resolutionis conveniently effected by recrystallization of compound VII or, moreeffectively, by the recrystallization of a suitable crystalline acidaddition salt of compound VII. Suitable acids include mineral acids,non-optically active hydrocarbyl monocarboxylic acids or hydrocarbyldicarboxylic acids. Especially preferable is oxalic acid. Therecrystallized acid addition salt is then decomposed by methods knownper se to afford the resolved amine VIII.

Compound VIII can be converted to compound Ia" by the method shown inStep F for the conversion of compound VII to compound Ia'. It ispreferable when dealing with optically active amines such as compoundVIII, to first convert them to the corresponding ether (IX) as shown inStep H. This is done by reaction of compound VIII with an excess of alower alkanol, preferably methanol, and a lower hydrocarbyl or aromaticaldehyde, preferably benzyaldehyde, in the presence of a catalyticamount of a weak inorganic base, preferably sodium bicarbonate. In thismanner, the valuable optically active amine is trapped as its reactionproduct with the aldehyde, and can be recycled for future use.

Conversion of compound IX to compound Ia" as shown in Step I isaccomplished according to the identical procedure of Step F.

The condensation of vinyl ketone addition products such as VII, VIII orIX with a 2-alkyl cycloalkane 1,3-dione is one of the key features ofthis reaction. It is in this condensation that specific stereochemicalinduction at one member of the critical C/D-ring junction of theeventual steroidal product occurs. Thus, this invention is particularlyadvantageous in that it involves a unique asymmetric induction. Theproducts of the condensation, i.e., the dienol ethers of formula Ia' andIa", have two asymmetric centers at positions 3 and 6a respectively,and, therefore, two racemates or four optical antipodes are possible.However, as a result of the condensation of this invention, when using aracemic starting material of formula VII, mainly one of the two possibleracemates of formula Ia' is formed. For synthesis of a racemic steroidalfinal product, both of the racemates can be used. When using theoptically active starting material of formulas VIII and IX, mainly asingle optical antipode of formula Ia" results. The specificity isincreased by using compounds of formula IX rather than those of VIII andthe desired optical antipode can be obtained in high purity byrecrystallization of the crude reaction product. This is another reasonfor the inclusion of the additional Step H in the Reaction sequence. Ithas been found that when starting with a compound of formula VIII or IXwith a 6-R-stereo-configuration, there is obtained the more desirableoptical antipode of formula Ia" having a 6aS(6aβ)-stereo-configuration.Thus, to prepare steroidal materials having the more desirable13β-stereo-configuration by the synthesis of this invention, one canstart with the antipode of formula Ia" which is prepared from antipodeVIII or IX which are in turn prepared by resolution of the racemic amineVII. The unique asymmetric induction concurrent to the condensation ofthis invention renders the obtention of a single optical antipode as anend-product more facile. The simultaneous formation of the dienol etherof formula Ia" with a unique asymmetric induction is a special advantageof this invention.

The keto dienes of formula Ia-1 ##STR8## where R₁ and m are aspreviously defined,

are readily converted to the corresponding 7β-alcohols and their estersand ethers as represented by the formula Ia-2 ##STR9## where R₁, R₇ andm are as previously defined,

by the sequence of reactions comprising reduction of the ketone to thealcohol and, if desired, subsequent esterification or etherification.

It is imperative that the reducing agent and the reaction conditions bechosen such that only the desired 7-ketone and not the cyano group onthe side chain is reduced. The reduction can be effected by the use of ametal hydride reducing agent. The use of an alkaline metal borohydride,e.g. sodium borohydride; an alkoxy substituted alkaline metalborohydride, e.g. trimethoxysodium borohydride; or an alkoxy substitutedcomplex metal hydride, e.g. lithium aluminum tri-t-butoxy hydride ispreferred.

This reaction is effected in any suitable reaction medium, such asethers, e.g. diethyl ether or tetrahydrofuran; water; a lower alkanol,e.g., methanol; N,N-di-(lower alkyl)-lower alkanoyl amides, e.g.N,N-dimethylformamide or aromatic amines, e.g. pyridine. The use of ahydrocarbon co-solvent, e.g. benzene, to solubilize the reactants issometimes necessary.

The remaining reaction conditions are not narrowly critical, although itis generally preferred to effect the reduction at reduced temperatures,i.e., below about room temperature. Temperatures in the range of fromabout 0° C. to about room temperature are normally employed.

The free alcohol is recovered from the reaction mixture after treatmentof the mixture with acid. The alcohol can be esterified in known manner,for example, by base-catalyzed reaction with a carboxylic acid halide orcarboxylic acid anhydride. Illustrative bases include inorganic basessuch as sodium hydroxide and potassium hydroxide and organic bases suchas a sodium alkoxide or an amine, especially a tertiary amine, and moreparticularly, pyridine and picoline.

The alcohol can also be etherified in a known manner by acid catalyzedreaction with an olefin such as isobutylene or 2,3-dihydropyran.Suitable acids include mineral acids, organic sulfonic acids and Lewisacids.

The keto dienes of formula Ia-1 can also be converted to their7β-hydroxy-7α-hydrocarbyl derivatives represented by the formula Ia-3.##STR10## where R₁, R₇ and m are as previously defined and R₈ ' is lowerhydrocarbyl,

by reaction of the keto diene with a hydrocarbyl magnesium halide suchas methyl magnesium chloride or vinyl magnesium chloride, or ahydrocarbyl alkali metal compound such as methyl lithium, sodiumacetylide, potassium acetylide, and the like.

It should be noted that where an alkenyl or alkynyl group is introducedinto the molecule at this time, it will be reduced to the correspondingalkyl group by the later hydrogenation steps of the present process.

It is well known that hydrocarbyl magnesium halides and hydrocarbylalkali metal compounds readily add to nitrile moieties such as thatpresent in the side chain of compound Ia-1. Surprisingly, it has beenfound that selective addition to the 7-keto function can be accomplishedby carrying out the reaction under carefully controlled conditions. Thereaction is run in an ethereal medium, e.g. ethyl ether ortetrahydrofuran, and in the case of alkynyl alkali metal, it isespecially convenient to perform the reaction in liquid ammonia. Thetemperature of the reaction is kept between -50° and +50°, preferably,between -20° and +10°. The resulting reaction product is hydrolyzed toproduce the free alcohol, which can be esterified as discussed above.

The next step of the general synthesis of the tricyclic compounds ofthis invention, comprises conversion of the diene of formula Ia to themonoene of formula Ib by catalytic hydrogenation. Suitable catalystsinclude the noble metals, such as platinum, palladium, rhodium, and thelike, as well as Raney nickel and other hydrogenation catalysts. Thesecatalysts can be employed in the form of the metal alone or can bedeposited on suitable support materials, such as carbon, alumina,calcium carbonate, barium sulfate, and the like. Palladium and rhodiumare preferred as catalysts. The hydrogenation is preferably conducted inthe presence of inert solvents, such as hydrocarbons, alcohols, ethers,and the like. The reaction conditions of pressure and temperature arenot narrowly critical, and normally a hydrogen pressure of about 1atmosphere and a temperature of about room temperature are employed.These ambient conditions are generally preferred to avoid significanthydrogenation of the 4a,9b(10b)-double bond and the labile nitrile groupof the side chain, although more severe conditions, for example up toabout 100° and up to about 10 atmospheres, can be employed if desired.The hydrogenation medium can be acidic, neutral, or basic, as may bedesired, although a hydrocarbon medium, e.g. toluene or hexane,containing a tertiary amine, e.g. triethylamine, is preferred for bestresults. It is not advisable to combine a high reaction temperature witha strongly acidic or basic reaction medium as significant hydrolysis ofthe labile nitrile group may occur. In the case of hydrogenation ofcompounds of formula Ia-2 where R₈ is an unsaturated hydrocarbylradical, the reaction, in addition to hydrogenating the ring doublebond, also hydrogenates the 7α-hydrocarbyl substituent, converting it toan alkyl group.

Via the aforesaid catalytic hydrogenation C/D-trans compounds are formedin a major proportion when hydrogenating a diene of formula Ia-2 orIa-3. This method thus provides an advantageous synthesis of C/D-transsteroidal materials. When hydrogenating a diene of formula Ia-1, C/D-ciscompounds are formed in a major proportion. This method thus provides anadvantageous synthesis of C/D-cis steroidal materials. The products ofhydrogenation of diene Ia-1 are shown as Ib-1, ##STR11## wherein R₁ andm are previously defined,

and those from hydrogenation of dienes Ia-2 and Ia-3 are shown as Ib-2,##STR12## wherein R₁, R₇, R₈ and m are as previously defined,

Compounds of structure Ib-1 can be converted to those of formula Ib-2 bythe identical techniques discussed above regarding the dienes of formulaIa.

When Z is carbonyl and the hydrogenation is effected under basicconditions, there is a tendency toward the production of predominantly6a/9a(10a)-cis compounds; that is, the hydrogen atom in the9a(10a)-position in formula Ib-1 is predominantly in the β- orientation.When these compounds are intended as intermediates for the synthesis ofsteroids having the C/D-trans-orientation, this technique is notparticularly desirable. Although the ratio of βto α-orientation is about1:1 at neutral conditions when hydrogenating a compound wherein Z iscarbonyl, it is preferred to hydrogenate a 7β-alcohol or ester offormula Ia-2 or Ia-3 because the products of this hydrogenation arepredominantly the 6a/9a(10a)-trans-compounds. When monoenes of formulaIb-1 having C/D-trans-configuration are desired, it is preferable tofirst reduce the dienone of formula Ia-1 to a corresponding hydroxycompound of formula Ia-2 prior to the catalytic hydrogenation. Followingthe catalytic hydrogenation, the carbonyl moiety in formula Ib-1 can beregenerated by conventional means, such as oxidation with chromiumtrioxide or silver carbonate.

The monoene compounds of formula Ib prepared by the above describedhydrogenation contain at least 3 asymmetric centers, at positions 3, 6aand 9a when m is 1 and at positions 3, 6a and 10a when m is 2. Withrespect to these three centers, there are thus eight stereoisomericconfigurations possible. By virtue of the unique asymmetric induction ofthis invention, proceeding from a racemic starting material of formulaVII only four of the stereoisomers of formula Ib are prepared, andproceeding from an optically active starting material of formula VIII orIX only two of the stereoisomers of formula Ib are prepared. Moreover,by the above-described hydrogenation of this invention and byappropriate selection of the 7-substituents in the diene of formula Iasubjected to the hydrogenation, there can predominantly be prepared thedesired 6a, 9a(10a)-trans-stereo-configuration. Thus, the eventualobtention of the more desired 13β-C/D-transconfiguration in the ultimatesteroidal product is rendered more facile by the stereo-selectivereactions provided by this invention.

Illustrative examples of the monoene of formula Ib include:

3-(3-cyanopropyl)-6a-methyl-2,3,5,6,6a,8,9,9a-octahydrocyclopenta[f][1]benzopyran-7(1H)-one,

3-(3-cyanopropyl)-6a-methyl-1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f][1]benzopyran-7β-ol,

3-(3-cyanopropyl)-6a-ethyl-2,3,5,6,6a,8,9,9a-octahydrocyclopenta[f][1]benzopyran-7(1H)-one,

3-(3-cyanopropyl)-6a-ethyl-1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f][1]benzopyran-7β-ol,

3-(3-cyanopropyl)-6a-methyl-1,2,3,5,6,6a,8,9,10,10a-decahydro-naphtho[2,1-b]pyran-7-one,

3-(3-cyanopropyl)-6a-methyl-1,2,5,6,6a,8,9,10,10a-decahydro-3H-naphtho[2,1-b]pyran-7β-ol,

3-(3-cyanopropyl)-6a7,8,9,10,10a-decahydro-naphtho [2,1-b]pyran-7-one,

3-(3-cyanopropyl)-6a-ethyl-1,2,5,6,6a,8,9,10,10a-decahydro-3H-naphtho[2,1-b]pyran-7β-ol.

The next reaction of applicants' general process for the compounds ofthis invention is the conversion of the monoene of formula Ib to theperhydro compound of formula Ic by the reaction of the monoene with acompound having the formula:

    R.sub.2 OH                                                 X

wherein R₂ is as previously defined.

That is, the monoene of formula Ib is reacted with water, a primaryalcohol, or a carboxylic acid. This reaction is catalyzed by mineral ororganic acids, for example, hydrochloric acid, phosphoric acid, sulfuricacid, para-toluene sulfonic acid, and the like. Sulfuric acid is thepreferred acid catalyst, and water, the preferred reactant. Although itis not necessary it is desirable to conduct this reaction in thepresence of an added solvent, particularly in the event the compound offormula X is water. In this case, it is desirable to employ a solventwhich is both miscible with water and a solvent for the monoene offormula Ib. Solvents of this nature include acetone, tert.-butylalcohol, dioxane and the like. The reaction temperature is not critical,and ambient temperature is normally employed although higher and lowertemperatures could be employed if desired.

As with the compounds of formulae Ia-1 and Ib-1, the compounds of thegeneral formula Ic wherein Z is carbonyl. ##STR13## and R₁, R₂ and m areas previously defined,

are readily converted to their corresponding 7β-alcohol or esters Ic-2##STR14## wherein R₁, R₂, R₇, R₈ and m are as previously defined,

by the previously described method.

In a modification of the general technique outlined above, one cansimultaneously effect the hydrogenation and hydration steps, forexample, by hydrogenation of a diene of formula Ia in aqueous sulfuricacid. When this simultaneous hydrogenation-hydration is effected, it ispreferred to begin with a diene having a hydroxyl group in the7β-position.

Illustrative examples of the compounds falling within the scope offormula Ic include:

3-(3-cyanopropyl)-6 a-methyl-4 a-hydroxyperhydrocyclopenta[f][1]benzopyran-7-one,

3-(3-cyanopropyl)-6 a-methyl-4 a-hydroxyperhydrocyclopenta[f][1]benzopyran-7β-ol,

3-(3-cyanopropyl)-6 a-methyl-4 a-hydroxyperhydrocyclopenta[f][1]benzopyran-7-one,

3-(3-cyanopropyl)-6 a-ethyl-4 a-hydroxyperhydrocyclopenta[f][1]benzopyran-7β-ol,

3-(3-cyanopropyl)-6 a-methyl-4 a-hydroxyperhydro-3H-naphtho[2,1-b]pyran-7-one,

3-(3-cyanopropyl)-6a-methyl-4a,,7β-dihydroxyperhydro-3H-naphtho[2,1-b]pyran,

3-(3-cyanopropyl)-6 a-ethyl-4 a-hydroxyperhydro-3H-naphtho[2,1-b]pyran-7-one,

3-(3-cyanopropyl)-6a-ethyl-4a,,7β-dihydroxyperhydro-3H-naphtho[2,1-b]pyran.

As indicated above, the tricyclic compounds of this invention are usefulas intermediates for the preparation of various medicinally valuablesteroid compounds. This is illustrated by the following Reaction Scheme.##STR15## where R₁, R₂, Z and m are as above; Z' is carbonyl or a groupof the formula ##STR16## where R₇ is as defined above and R₉ is hydrogenor lower alkyl; Z" is a group of the formula ##STR17## where R₇ and R₉are as defined above, or a group of the formula ##STR18## where R₁₅ 'and R₁₅ " are each independently the same lower alkyl or taken togetherare lower alkylene having from 1 to 4 carbons; and R₁₄ is hydrogen,lower hydrocarbyl, aryl, or aryl lower alkyl.

    __________________________________________________________________________    CHART FOR REACTION SCHEME II                                                  Reagents                 Solvents            Conditions                       Step                                                                              Operable    Preferred                                                                              Operable   Preferred                                                                              Operable                                                                            Preferred                                                                           Remarks              __________________________________________________________________________    J   chromic acid; alkali                                                                      chromic acid                                                                           ketones, e.g.                                                                            acetone,  -20°                                                                        0° to                                                                  30°                     metal dichromates,                                                                        sulfuric acid                                                                          acetone; ethers, e.g.                                                                    acetic acid                                                                            to                                   e.g.,potassium di-                                                                        (Jones reagent)                                                                        diethyl ether; lower                                                                              +100°                         chromate; alkali metal                                                                             organic acids, e.g.                                      permanganate,e.g.,   acetic acid; pyri-                                       potassium permanganate                                                                             dine; dimethyl-                                                               formamide; mixtures                                                           of the above with                                                             water                                                K   mineral acids, e.g.,                                                                      catalytic                                                                              lower alkanols, e.g.,                                                                    methanol  20°                                                                          50°                                                                         For acid                 sulfuric acid; organic                                                                    amount of                                                                              methanol; hydro-    to    to    catalyzed                sulfonic acids; e.g.,                                                                     sodium hydrox-                                                                         carbons,e.g.,toluene                                                                              150°                                                                         100°                                                                         reaction it              para-toluenesulfonic                                                                      ide                                      is prefer-               acid; alkali metal                                   able to re-              hydroxides,e.g.,sodium                               move water               hydroxide                                            of reaction                                                                   by azeotro-                                                                   pic distil-                                                                   lation               L   metal catalysts                                                                           palladium-char-                                                                        lower alkanols, e.g.,                                                                    tetrahydro-                                                                            0° to                                                                        20° to                  in presence of a min-                                                                     coal in the                                                                            methanol; ethers,                                                                        furan    100°                                                                         30°                     eral acid, an alkali,                                                                     presence of an                                                                         e.g.,tetrahydro-    up to 1 to 3atm                      metal hydroxide or an                                                                     organic amine,                                                                         furan; lower organic                                                                              10° atm                       organic amine                                                                             e.g. triethyl-                                                                         acids, e.g.,acetic                                                   amine    acid; hydrocarbons,                                                           e.g.,benzene                                         M   a. lower alkanols,e.g.                                                                    a. ethylene                                                                            ethers, e.g.,tetra-                                                                      tetrahydro-                                                                             0 ° to                                                                      20°                     methanol; lower alkylene                                                                  glycol   hydrofuran; hydro-                                                                       furan    100°                                                                         to                             diols, e.g.,ethylene carbons, e.g.,            50°                     glycol, 2,3-butanediol;                                                                            toluene; lower                                           b. catalytic amounts of                                                                   b. sulfuric                                                                            alkanols, e.g.,                                          either mineral acids,e.g.                                                                 acid     methanol                                                 sulfuric acid; organic                                                        sulfonic acids, e.g.,                                                         para-toluenesulfonic                                                          acid, or Lewis acids,                                                         e.g., borontrifluoride;                                                       c. tri(lower alkyl)                                                                       c. trimethyl-                                                     orthoformates                                                                             orthoform-                                                                    ate                                                           N   organomagnesium halides,                                                                  methyl lithium                                                                         ethers, e.g.,diethyl                                                                     diethyl ether                                                                          -50°                                                                         -10°                    e.g.,methylmagnesium ether, tetrahydro-                                                                       or tetrahydro-                                                                         to    to                             chloride; organo alkali                                                                            furan; hydrocarbons,                                                                     furan    +50°                                                                         +10°                    metal reagents, e.g.,                                                                              e.g.,hexane, toluene                                     methyl lithium                                                            O   dilute mineral acids,                                                                     dilute hydro-                                                                          lower alkanols, e.g.,                                                                    methanol  20°                                                                         50°                     e.g.,hydrochloric acid;                                                                   chloric acid                                                                           methanol; ethers,   to    to                             organic sulfonic acids,                                                                            e.g.,tetrahydrofuran                                                                              100°                                                                         70°                     e.g.para-toluene-                                                             sulfonic acid                                                             __________________________________________________________________________

In the first step of this reaction scheme (J), compounds of formula Icare oxidized to form bicyclic compounds of the formula XI by contactwith such oxidizing agents such as chromic acid, potassium dichromate,or potassium permanganate, Jones reagent (chromic acid, sulfuric acidand acetone), or a chromic acid-acetic acid mixture are preferred asoxidizing agents. The nature of Z is unchanged in this reaction, exceptwhere Z is hydroxy methylene [--CH(OH)--]. In this instance, unless thehydroxyl group is protected, as by formation of a lower acyl ester, itis oxidized to form a carbonyl group. One can then obtain a hydroxylatedproduct by hydrolysis of the product ester. Because of the labile natureof the nitrile group on the side chain, care must be taken to controlthe reaction conditions, especially when using a strongly acidicoxidizing medium such as Jones reagent. It is preferred to effecthydration and oxidation in one step without isolating the intermediatehydration product.

In the second step (K) bicyclic compound XI is treated with acid or baseto effect cyclization to XII. When acid is used as the catalyst, it ispreferred that the water of reaction be removed, as by refluxing thereaction mixture with an azeotropic agent and separating the water fromthe condensate. It is preferred to effect the cyclization by a basecatalyzed dehydration using only a catalytic amount of a base, mostpreferably an alkali metal hydroxide. The use of only a small amount ofbase is critical to this reaction because of the base sensitive natureof the nitrile group.

The hydrogenation of cyclo-olefin XII to tricyclic compound XIII (L) ispreferably effected with a noble metal catalyst, e.g. apalladium-charcoal catalyst or a rhodium catalyst. The reaction can becarried out either in a neutral, acidic,, or basic medium and bestresults are obtained when the reaction is conducted in the presence of abase, preferably an organic amine. The other reaction conditions oftemperature and pressure are chosen so that only the desired double bondis reduced and the potentially reducible nitrile group is leftuntouched. During this hydrogenation reaction, an alkenyl or alkynylgroup substituted in the 7α-position of compound XII is reduced to thecorresponding alkyl group.

Compound XIII is next reacted (M) with either a lower alkanol or loweralkylene diol in the presence of a strong acid and a tri(lower alkyl)orthoformate to afford a ketal of structure XIV. Where Z' in compound XVis a carbonyl group, it is also ketalized. When the ketalizing agent isa lower alkanol there may be formed in addition to compound XIV an enolether of structure XVII. ##STR19## where R₁, R₁₅, Z" and m are as above.

Compounds of formula XIV and XVII need not be separated and can becarried through the remainder of the synthetic sequence as a mixture.

With all of the potential carbonyl groups of compound XIV protected asketals or enol ethers, the nitrile group is reacted with an organometallic reagent followed by an aqueous work-up as shown in Step N toafford a tricyclic ketone of structure XV. If, in compound XIV, Z" is agroup wherein R₇ is acyloxy, such a group will be converted to a hydroxygroup by the reaction conditions of Step N. Reacylation of this hydroxygroup can be effected at a later stage.

In a final step (O), the protective ketal groups of compound XV areremoved and the resulting compound is cyclized to the steroid ofstructure XVI. This is conveniently done by treating compound XV with anaqueous acid, preferably a mineral acid or an organic sulfonic acid.Steroids of structure XVI are well known intermediates for thepreparation of medicinally valuable steroids.

For example, compounds of formula XVI can be selectively alkynylated bysuitable organometallic acetylides affording norgestrel(13β-ethyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one). Exemplary of thesuitable alkynylating agents to effect the conversion to norgestral arethe alkali acetylides such as lithium acetylide, potassium acetylide,sodium acetylide, etc. The reaction is carried out in the presence ofliquid ammonia in a suitable solvent such as for example, benzene ortoluene. The alkynylation is effected preferably at reflux temperatureof the reaction medium although temperatures from between -60° to -30°are suitable. Exemplary of other suitable reagents to effect theacetylenic addition are lithium acetylide-ethylene diamine complex indimethylformamide solvent and Grignard analogs such as mono and bisacetylene magnesium halides. The acetylene addition, known with13-methyl-substituted steroids, is similarly effected with a more bulky13-ethyl-substituted steroids notwithstanding the increased sterichindrance in the latter configuration.

Compound of formula XVI wherein Z is carbonyl can be converted intocorresponding pregnane compounds, i.e., compounds in which Z is of theformula ##STR20## by known procedures. Thus, for example,19-nor-14β-andros-4-en-3,17-dione can be converted into19-nor-14β,17α-progesterone and des-A-androst-9-en-5,17-dione can beconverted into des-A-pregn-9-en-5-one. These procedures for convertingandrost-17-ones into pregnanes are best effected if all carbonyl groupsother than that in the 17-position are initially protected.

An alternative synthesis for steroids of structure XVI from tricycliccompounds of structure Ia involving the intermediacy of known compoundsof structure XVII is depicted in Reaction Scheme III. Compounds ofstructure XVII can be prepared from those of structure Ia by reactionwith an organo metallic agent followed by an aqueous work-up as shown inReaction Step P. This process is carried out in an identical manner tothat shown in Reaction Step N from Reaction Scheme II. If one desirescompounds of structure XVII where Z is a carbonyl group, it is advisableto first protect the carbonyl group in compound IA-1 as a ketal bymethods known per se and, after the completion of reaction Step P, theketal can be hydrolyzed back to the carbonyl group. If one starts withcompounds of structure Ia-2 or Ia-3, where R₇ is an acyl group, such agroup will be hydrolyzed during the course of Reaction Step P to ahydroxy group. Such a hydroxy group can, if desired, be reacylated inthe usual manner. Where, in compound XVIII, Z contains an R₈ group whichis alkenyl or alkynyl, such a group will be reduced to the correspondingalkyl group during the later conversion of compound XVII to steroids ofthe structure XVI. ##STR21##

    __________________________________________________________________________    CHART FOR REACTION SCHEME III                                                 Reagents               Solvent         Conditions                             Step                                                                              Operable   Preferred                                                                             Operable   Preferred                                                                          Operable                                                                              Preferred                                                                             Remarks                __________________________________________________________________________    P   THE SAME AS IN STEP N                                                     Q   a. lower alkanols, e.g.                                                                  a. methanol                                                                           lower alkanols, e.g.                                                                     methanol                                                                           0° to 100°                                                              20° to 30°           methanol           methanol; ethers,                                          b. lower alkyl ortho-                                                                    b. trimethyl-                                                                         e.g. tetrahydrofuran.                                      formates, e.g.                                                                           ortho-                                                             trimethylortho-                                                                          formate                                                            formate                                                                       c. mineral acids, e.g.                                                                   c. boron-                                                          sulfuric acid;                                                                           trifluor-                                                          organic sulfonic                                                                         ide                                                                acids, e.g. para-                                                             toluene-sulfonic                                                              acid; Lewis acids,                                                            e.g. boron tri-                                                               fluoride.                                                                 R   THE SAME AS IN STEP N                                                     S   THE SAME AS IN STEP F                                                     __________________________________________________________________________

An alternative synthesis of compounds of structure XVII is depicted inReaction Scheme III starting with compounds of structure VII. In thefirst step, Reaction Step Q, the hemiketal function of compound VII isprotected as the ketal function by reaction with a lower alkanol and atri(lower alkyl) orthoformate in the presence of a strong acid such as aLewis acid, preferably boron trifluoride.

In the next step (R) compound XVIII is reacted with an organo metallicagent followed by an aqueous work-up to afford a compound of structureXIX. This reaction is carried out in the same manner as that shown inStep N of Reaction Scheme II. The resulting ketone is then reacted inStep S with a 2-alkylcycloalkan-1,3-dione in a manner identical withthat shown in Step F of Reaction Scheme I to afford compounds ofstructure XVII where Z is carbonyl.

In the claims, all compounds shall be construed to include,independently, the racemic form of the compound and independently, eachenantiomeric form, i.e., d and l configurations unless specificallyindicated otherwise.

The following examples are illustrative. All temperatures are in degreesCentigrade and all products having centers of asymmetry are racemicunless specifically indicated otherwise.

EXAMPLE 1

A solution of 347.4 g. (1.67 moles) of2,2-di-(3-cyanopropyl)-1,3-dioxolane in 1.5 l. of acetone was cooled to10° and treated with 1 l. of a cold (10°) 3N aqueous hydrochloric acidsolution. The mixture was allowed to stand at room temperature for 18hours then concentrated to a volume of approximately 1.5 l. at 40° andaspirator pressure. The organic materials were extracted with methylenechloride (1 × 600 ml. and 3 × 300 ml.) and the combined organic extractswere washed with saturated brine (2 × 200 ml.) dried and concentrated atreduced pressure giving 276 g. of oily 5-oxoazeleonitrile.

A sample of this material on distillation yielded pure5-oxoazeleonitrile, b.p. 137°-140°/0.05 mm., as a colorless liquid. ir:ν_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N) and 1710 (C═O) cm⁻¹.

Anal. calcd. for C₉ H₁₂ N₂ O: C, 65.83; H, 7.37; N, 17.06; Found: C,66.08; H, 7.46; N, 17.07.

EXAMPLE 2

A solution of 276 g. (1.67 moles) of crude 5-oxoazeleonitrile in 500 ml.of methanol and 500 ml. of water was added to a cooled (5°), stirredsolution of 33 g. (0.873 mole) of sodium borohydride in 300 ml. ofwater. The temperature was held at 5°-10° during the addition. Afteraddition was complete, the mixture was stirred at room temperature 90minutes.

Dilute aqueous sulfuric acid solution (4N) was added to the reactionmixture with cooling (10° ) until pH 2-3. The organic materials wereextracted with methylene chloride (1 × 500 ml., 2 × 250 ml. and 2 × 125ml.). The combined organic extracts were washed with brine (1 × 200 ml.)and dried. Removal of solvents at reduced pressure gave 272 g. (98%) of5-hydroxyazeleonitrile as a colorless, mobile liquid.

A sample of this material on evaporative distillation gave an analyticalspecimen, b.p. 145°-175° (bath temp.)/0.01 mm. ir: ν_(max)^(CHCl).sbsp.3 3625, 3500 (OH) and 2250 (C.tbd.N) cm⁻¹.

Anal. calcd. for C₉ H₁₄ N₂ O: C, 65.03; H, 8.49; N, 16.85; Found: C,64.92; H, 8.35; N, 16.68.

EXAMPLE 3

A solution of 272 g. (1.64 moles) of crude 5-hydroxyazeleonitrile in 1.5l. of toluene was treated with 312 g. (1.64 moles) of p-toluenesulphonicacid monohydrate and the mixture was stirred and refluxed for 1 hour.The starting materials dissolved and were replaced by a precipitate ofammonium tosylate which, after cooling was filtered off with suction andwashed with fresh toluene (2 × 500 ml.).

The combined filtrate and washings were washed with water (3 × 100 ml.)driedand concentrated at reduced pressure. The residue on distillationfurnished pure 8-cyano-5-hydroxyoctanoic acid lactone (214 g.; 78.2%),b.p. 162°-165°/0.2 mm. ir: ν_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N), 1730and 1250 (δ-lactone) cm⁻¹.

Anal. calcd. for C₉ H₁₃ NO₂ : C, 64.65; H, 7.84; N, 8.38; Found: C,64.63; H, 7.89; N, 8.18.

Similar results were obtained when one mole equivalent of concentratedsulfuric acid and one mole equivalent water were substituted for thep-toluenesulphonic acid monohydrate.

EXAMPLE 4

A stirred solution of 8.35 g. (0.05 mole) of 8-cyano-5-hydroxyoctanoicacid lactone in 40 ml. of dry tetrahydrofuran (THF) was cooled to -70°and treated over 14 minutes with 3 ml. (0.076 mole) of a solution ofvinylmagnesium chloride in THF (2M). The mixture was then stirred for 6minutes at -50°, cooled to -65° and decomposed with 2 ml. of methanoland subsequently with aqueous ammonium chloride solution (5%; 50 ml. --the cooling bath was removed for the last addition and the temperaturerose to 10°). Sufficient acetic acid was added to yield two clear layers(pH still on basic side).

The organic layer was separated and the aqueous layer was extracted withTHF (100 ml. and 2 × 50 ml.) and the combined THF solutions containing6-(3-cyanopropyl)-2-vinyltetrahydropyran-2-ol were treated with 10 ml.of diethylamine and left at room temperature for 1.5-2 hours. Removal ofsolvents at reduced pressure yielded crude2-(2-diethylaminoethyl)-6-(3-cyanopropyl)-tetrahydropyran-2-ol (17 g.)as an oil.

This material was treated with 50 ml. of 10% aqueous acetic acid and 2ml. of ether. The aqueous layer was reextracted with 2 ml. of additionalether and the combined ether extracts were reextracted with 10% aqueousacetic acid (2 × 25 ml.) then discarded. The combined aqueous acidextracts was made alkaline with 10% aqueous sodium carbonate solutionand the Mannich base was isolated by extraction with methylene chloride(5 × 20 ml.). Solvent removal at reduced pressure gave the pure2-(2-diethylaminoethyl)-6-(3-cyanopropyl)-tetrahydropyran-2-ol (10.84g.; 81%) as a mobile, pale-yellow oil. ir: ν_(max) ^(film) 3150, 3450(bonded OH and NH), 2250 (C.tbd.N), 1710 (weak C═O of open form).

Anal. calcd. for C₁₅ H₂₈ N₂ O₂ : C, 67.12; H, 10.52; N, 10.44; Found: C,67.15; H, 10.37; N, 10.28.

EXAMPLE 5

A solution of 18.92 g. (0.0706 mole) of Mannich base from Example 4,8.72 g. (0.778 mole) of 2-methyl-1,3-cyclopentandione 64 ml. of glacialacetic acid and 253 ml. of toluene was stirred and refluxed for 1.5hours. After cooling, the solution was washed twice with 100 ml.portions of water, once with 100 ml. of 0.5N aqueous HCl, twice with 100ml. portions of saturated aqueous sodium bicarbonate, dried, filteredand concentrated at reduced pressure giving 16.3 g. (85.4%) of orangesolid dienolether mixture which was essentially homogeneous on tlcanalysis. Recrystallization from 20 ml. of ethanol gave 11.54 g. (60.4%)of pale orange crystals, m.p. 95°-99°. By further recrystallization of asample from ethanol on anaytical specimen of3-(3-cyanopropyl)-6a-methyl-1,2,3,5,6,6a-hexahydrocyclopenta-[f][1]benzopyran-7(8H)-onewas obtained as pale-yellow crystals, m.p. 100°-101.5°. uv: λ_(max)^(EtOH) 253 mμ (ε19500); ir: ν_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N), 1730(C═O), 1630 (C═C) cm⁻¹ ; nmr: δ_(TMS) ^(CDCl).sbsp.3 5.47 (triplet, J=2Hz, H--C═C, 1 proton), 3.85 (multiplet, H--C--O, 1 proton), 1.14(singlet, C₆ --CH₃, 3 protons) ppm; Mass spectrum m/e 271 (M⁺).

Anal. calcd. for C₁₇ H₂₁ NO₂ : C, 75.24; H, 7.80; N, 5.16; Found: C,75.36; H, 7.75; N, 5.03.

EXAMPLE 6

A solution of 6 g. (0.0222 mole) of dienolether from Example 5 in 35 ml.of benzene was added dropwise, over a 10 minute period to an ice-coldsolution of 0.864 g. (0.0228 mole) of sodium borohydride in 50 ml. ofethanol and 5 ml. of water. The resulting mixture was stirred withice-bath cooling for 25 minutes then the cooling bath was removed andthe mixture was stirred at ambient temperature for an additional 15minutes. The mixture was poured into aqueous brine and the organic layerwas separated. The aqueous layer was extracted twice with ether. Thecombined organic solutions were washed once with brine, dried andconcentrated at reduced pressure giving 6 g. of yellow, solid3-(3-cyanopropyl)-6a-methyl-1,2,3,5,6,6a,7,8-octahydrocyclopenta-[f][1]benzopyran-7β-ol.TLC analysis showed a single spot and the absence of starting ketone.ir: ν_(max) ^(CHCl).sbsp.3 3450, 3600 (OH), 2250 (C.tbd.N), 1640(dienolether) cm⁻¹.

EXAMPLE 7

The above crude alcohol from Example 6 (6 g.) in 35 ml. of toluene and25 ml. of tetrahydrofuran was hydrogenated over 1 g. of preequilibratedAK-4 5% palladium on carbon at room temperature and 1 atm. for 23 hours.A total of 543 ml. of hydrogen was consumed (555 ml. theory for 0.022mole). The catalyst was filtered with suction on a pad of Celite and thefilter cake was washed well with toluene. The combined filtrate andwashes were concentrated at reduced pressure giving 6.65 g. of6a,9a-trans-3-(3-cyanopropyl)-6a-methyl-1,2,3,5,6a,7,8,9,9a-decahydrocyclopenta[f][1]benzopyran-7β-olas a pale-yellow foam. ir: ν_(max) ^(film) 3480 (OH), 1680 (enolether).2250 (C.tbd.N) cm⁻¹. The peak due to the dienolether at 1640 cm⁻¹ wascompletely absent.

EXAMPLE 8

The above crude enolether from Example 7 (6.65 g.) was dissolved in 165ml. of acetone and treated with 15 ml. of 0.5N aqueous sulfuric acidsolution. The resulting solution was stirred at room temperature for 3.5hours. This solution containing6a,9a-trans-3-(3-cyanopropyl)6a-methyl-perhydrocyclopenta[f][1]benzopyran-4a,7β-diolwas then cooled using an ice-bath and treated with 16.5 ml. of Jonesreagent (4N with respect to OH groups), dropwise, over 15 minutes. Theice-bath was removed and the resulting red mixture was stirred at roomtemperature for 3 1/4 hours. After decomposition of the excess oxidantwith sodium bisulfite, the mixture was diluted with brine and benzeneand the organic layer was separated. The aqueous layer was extractedthree times with benzene and once with ether. The combined organicsolutions were washed three times with saturated aqueous sodiumbicarbonate solution and the combined washings were back extracted oncewith ether. The total organic solution was dried, filtered andconcentrated at reduced pressure giving 5.93 g. (92.5%) of4-(3-oxo-6-cyano-1-hexyl)-3a,4,7,7a-tetrahydro-7a-methyl-1,5(6H)-indandioneas an orange oil. ir: ν_(max) ^(film) 2250 (C.tbd.N), 1745(cyclopentanone C═O), 1715 (cyclohexanone and aliphatic C═O) cm⁻¹. TLCanalysis showed the major spot due to the triketone with R_(f) 0.28.

EXAMPLE 9

A solution of 3.983 g. (0.01066 mole) of crude triketone prepared inExample 8 in 20 ml. of methanol was treated with 1 ml. of 0.1Mmethanolic potassium hydroxide solution. The resulting dark brownsolution was stirred and refluxed for 2 hours. After cooling, thereaction mixture was poured into brine and extracted twice with etherand once with methylene chloride. The combined organic extracts weredried, filtered and concentrated at reduced pressure giving 2.8 g.(93.8%) of crudetrans-anti-6-(2-cyanoethyl)-3a-methyl-1,2,3a,4,5,9,9a,9b-octanhydro-3H-benz[e]inden-3,7(8H)-dioneas a brown solid. Recrystallization from ethanol gave 1.5 g. (50.2%) ofpale yellow crystals, m.p. 105°-107° (homogeneous on tlc analysis, R_(f)0.33). The analytical specimen was obtained as white crystals, m.p.106°-107°, by further recrystallization of a sample from ethanol. ir:ν_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N), 1740 (cyclopentanone C═O), 1665(cyclohexanone C═O), 1605 (C═C) cm⁻¹ ; uv: λ_(max) ^(EtOH) 245 (ε15640)mμ, nmr: δ_(TMS) ^(CDCl).sbsp.3 1.03 (singlet, C₁₃ --CH₃) ppm.

Anal. Calcd. for C₁₇ H₂₁ NO₂ : C, 75.24; H, 7.80; N, 5.16; Found: C,75.52; H, 7.99; N, 5.08.

EXAMPLE 10

A solution of 2.853 g. (0.0099 mole) of crude triketone prepared inExample 8 and 0.637 g. of p-toluenesulfonic acid monohydrate in 130 ml.of toluene was stirred and refluxed, under nitrogen using a Dean-Starktrap for 4.5 hours after vigorous refluxing began. The mixture wasallowed to stir at room temperature for 13.5 hours then washed twicewith saturated aqueous sodium bicarbonate solution. The combinedwashings were back extracted twice with methylene chloride. The combinedorganic solutions were dried, filtered and concentrated at reducedpressure giving 2.728 g. of an orange semi-solid residue.

This material was triturated under ethyl acetate and the solid wassuction filtered and washed until essentially colorless with ethylacetate. The combined filtrate and washings were concentrated at reducedpressure and the residue chromatographed on 100 g. of silica gel. Thefractions eluted with 4:1 benzene: ether gave 0.866 g. (32.3%) ofcrystalline6-(2-cyanoethyl)-3a-methyl-1,2,3a,4,5,9,9a,9b-octanhydro-3H-benz[e]inden-3,7(8H)-dione.This was recrystallized from ethanol giving 0.681 g. of pale-yellowsolid, m.p. 105°-107°.

EXAMPLE 11

A solution of 1.03 g. (3.82 moles) of enedione prepared in Example 9 in25 ml. of dry tetrahydrofuran and 0.7 ml. of triethylamine was stirredin an atmosphere of hydrogen over 0.25 g. of preequilibrated AK-4 5%palladium on carbon. After 40 minutes, 101 ml. of hydrogen was absorbed(96 ml. theory) and the hydrogenation was stopped. The catalyst wasfiltered and washed with ether and the combined filtrate and washingswere concentrated at reduced pressure giving 1 g. of colorless, solidresidue. This was crystallized from ethanol giving 805 mg. (77.4%) ofcolorlesstrans-anti-trans-anti-6-(2-cyanoethyl)-3a-methyl-1,2,3a,4,5,5a,8,9,9a,9b-decahydrobenz[e]inden-3,7(6H)dione,m.p. 130°-132° TLC analysis showed a single spot, R_(f) 0.31 (no uv.).An analytical specimen was obtained, m.p. 132°-133°, by furtherrecrystallization from ethanol.

ir: ν_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N), 1740 (cyclopentanone C═O),1710 (cyclohexanone C═O) cm⁻¹ ; nmr: δ_(TMS) ^(CDCl).sbsp.3 0.98(singlet, C_(3a) --CH₃) ppm; mass spectrum m/e 273 (M⁺).

Anal. calcd. for C₁₇ H₂₃ NO₂ : C, 74.69; H, 8.48; N, 5.12; Found: C,74.49; H, 8.49; N, 5.05.

EXAMPLE 12

A solution of 0.1 g. (0.366 mole) of cyanodione prepared in Example 11,0.22 ml. of trimethylorthoformate, 0.02 ml. of borontrifluoride etherateand 10 ml. of methanol and stirred at room temperature for 0.5 hoursthen poured into excess saturated, aqueous sodium bicarbonate solutionand extracted three times with ether. The combined ether extracts werewashed with brine, dried, filtered and concentrated at reduced pressuregiving 0.121 g. of an oil. TLC analysis showed an elongated spot, R_(f)0.48 and no starting material present. ir: ν_(max) ^(film) 2250(C.tbd.N), 2840 (OCH₃), 1680 (enolether), 1160, 1110, 1080, 1050 cm⁻¹(no OH, essentially no C{O). The nmr spectrum showed OCH₃ singlets atδ_(TMS) ^(CDCl).sbsp.3 3.28, 3.24 and 3.22 ppm and a weak band at δ3.50possibly due to the vinyl proton of an enolether. The integrationindicated 3 OCH₃ groups per molecule.

The mixture appeared to consist oftrans-anti-trans-anti-3,3,7,7-tetramethoxy-3a-methyl-6(2-cyanoethyl)perhydro-1H-benz[e]indeneand an enol ether at the 6,7- or 7,8-position resulting from loss of onemolecule of methanol.

EXAMPLE 13

A solution of 0.134 g. of the crude ketl-enolether mixture from Example12 in 10 ml, of anhydrous ether was stirred with cooling in an ice-saltbath at -10°-0° while 0.8 ml. (1.6 moles) of 2M ethereal methyllithiumwas quickly added from a syringe. The resulting mixture was stirred at-10°-0° for 1.5 hours then treated with saturated aqueous ammoniumchloride solution. The ether layer was separated and the aqueous layerwas extracted twice with ether. The combined ether solutions were washedwith saturated brine, dried, filtered and concentrated at reducedpressure. This gave 0.147 g. of pale-yellow oily mixture oftrans-anti-trans-anti-3,3,7,7-tetramethoxy-3a-methyl-6(3-oxo-1-butyl)perhydro-1H-benz[e]indeneand the corresponding enol ether. The infrared spectrum indicated thereaction was complete: ν_(max) ^(film) 2835 (OCH₃), 1710 (ketone C═O),1680 (enolether) cm⁻¹ (no C.tbd.N).

EXAMPLE 14

A solution of 0.1 g. (0.366 mole) oftrans-anti-trans-anti-6-(2-cyanoethyl)-3a-methyl-1,2,3a,4,5,5a,8,9,9a,9b-decahydrobenz[e]inden-3,7(6)dione in 5 ml. of dry tetrahydrofuran was treated with0.226 g. (3.66 moles) of ethylene glycol, 0.2 ml. of trimethylorthoformate and 0.01 ml. of concentrated sulfuric acid. The resultingsolution was stirred at room temperature under nitrogen, for 1.5 hoursthen poured into excess 10% aqueous sodium hydroxide solution. Afterdilution with brine, the mixture was extracted three times with ether.The combined either extracts were washed with brine, dried, filtered andconcentrated at reduced pressure giving 133 mg. of colorless,crystalline product. TLC analysis showed a major spot, R_(f) 0.50 and avery weak impurity R_(f) 0.76. No starting material, R_(f) 0.40 wasdetectable.

This material was combined with the product from an identical run (0.111g.; 0.244 g. total) and chromatographed on 25 g. of silica gel. Thefractions eluted with 1:1 benzene:ether gave 0.229 g. (86.8%) of puretrans-anti-trans-anti-3,3,7,7-bis(ethylenedioxy)-3a-methyl-6-(2-cyanoethyl)perhydro-1H-benz[e] indene asa colorless solid. (TLC, R_(f) 0.5). Two recrystallizations from ethergave colorless crystals, m.p. 118.5°-120.5°. ir: ν_(max) ^(CHCl).sbsp.32250 (C.tbd.N), 1160, 1105, 1050 cm⁻¹ ; nmr: δ_(TMS) ^(CDCl).sbsp.33.94, 3.86 (singlets, 8 ethylene ketal protons), 0.87 (singlet, C_(3a)--CH₃) ppm; mass spectrum m/e 361 (M⁺).

Anal. calcd. for C₂₁ H₃₁ NO₄ : C, 69.77; H, 8.65; N, 3.88; Found: C,69.87; H, 8.39; N, 3.86.

EXAMPLE 15

An ethereal methyllithium solution (4.3 ml.; 2M; 8.6 moles) was cooledto -10° (ice-salt bath) and stirred while a solution of 0.711 g. (1.97moles) of bis-ketal nitrile prepared in Example 14 in 15 ml. ofanhydrous ether and 5 ml. of anhydrous tetrahydrofuran was added over a3 minute period. The reaction mixture was stirred at -5° for 1 hour then10 ml. of water was added and stirring was continued at room temperaturefor 30 minutes. After dilution with saturated brine, the ether layer wasseparated and the aqueous layer was extracted with ether. The combinedeither layers were washed with brine, dried, filtered and concentratedat reduced pressure giving 0.719 g. (96.5%) of essentially puretrans-anti-trans-anti-3,3,7,7-bis(ethylenedioxy)-3a-methyl-6-(3-oxo-1-butyl)perhydro-1H-benz[e]indeneas a colorless solid. TLC analysis showed essentially one spot R_(f)0.37.

A sample was chromotographed on silica gel and recrystallized from ethergiving fluffy white solid, m.p. 122°-123°. ir: ν_(max).sup. CHCl.sbsp.31715 (aliphatic ketone C═O), 1160, 1105, 1050, 1040, 950 cm⁻¹.

EXAMPLE 16

A solution of 0.088 g. (0.23 mole) of the crude mixture from Example 13in 5 ml. of methanol and 1 ml. of 4N aqueous hydrochloric acid solutionwas stirred and refluxed for 4 hours. After cooling, the reactionmixture was diluted with benzene and washed with saturated brine. Theorganic layer was dried, filtered and concentrated at reduced pressuregiving 0.063 g. of crude, crystalline 19-norandros-4-en-3,17-dione. TLCanalysis showed the main spot R_(f) 0.27 (identical R_(f) to that ofauthentic 19-norandrostendione) and a minor impurity, R_(f) 0.42.

This material was chromatographed on 5 g. of silica gel. The fractionseluted with 4:1 and 1:1 benzene:ether afforded 0.053 g. (84.8%) ofcolorless crystals which were homogeneous on TLC analysis.Recrystallization from aqueous methanol gave 0.038 g. (60.8%) ofcolorless crystals, m.p. 155°-157°. ir: ν_(max) ^(CHCl).sbsp.3 1735(cyclopentanone C═O), 1665 (enone C═O), 1620 (C═C)⁻¹ ; uv: λ_(max)^(EtOH) 240 mμ (ε15650).

EXAMPLE 17

A solution of 0.538 g. (1.47 moles) of bis-ketal from Example 15 in 20ml. of methanol and 6 ml. of 4N aqueous hydrochloric acid was stirredand refluxed for 4 hours, then cooled, diluted with brine and extractedthree times with ether. The combined ether extracts were washed withbrine, dried, filtered and concentrated at reduced pressure giving 0.352g. (87%) of colorless, crystalline 19-norandrostendione. This materialwas homogeneous on TLC analysis, R_(f) 0.36. Recrystallization fromaqueous methanol gave 0.254 g. (62.7%) of colorless crystals, m.p.155°-156.5°. uv: λ_(max) ^(EtOH) 240 mμ (ε17400).

EXAMPLE 18

An 18.0 g. sample of 2-ethylcyclopentan-1,3-dione was dissolved in 500ml. of 4:1 toluene:glacial acetic acid and treated with a solution of20.15 g. of Mannich base from Example 4 in 200 ml. of 4:1toluene:glacial acetic acid. The resulting solution was stirred andheated under reflux for 0.5 hour then refluxed azeotropically for 1.5hour using a Dean-Stark trap. After cooling to room temperature, themixture was diluted with 100 ml. of toluene and washed with water (2 ×200 ml.). Each aqueous portion was reextracted with toluene (2 × 200ml.). The combined organic extracts were washed with saturated brine (1× 200 ml.) then dried, filtered and concentrated at reduced pressuregiving 20.38 g. (93.5%) of3-(3-cyanopropyl)-6a-ethyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][1]benzopyran-7(8H)-onewhich showed one spot, R_(f) 0.50, on TLC analysis.

From another experiment, on a smaller scale, using the same procedure asabove, the crude product was purified by chromatography on silica gel.Elution with 9:1 and 4:1 benzene: ether gave pure dienolether mixture.

ir: λ_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N), 1730 (cyclopentanone) (C{O),1640 (dienolether) cm⁻¹ ; uv: λ_(max) ^(EtOH) 254 mμ (ε12650); nmr:δ_(TMS) ^(CDCl).sbsp.3 5.51 (triplet, J=2Hz, --CH═C, 1 proton), and 3.80(multiplet, C₃ --H, 1 proton), 2.94 (multiplet, C₈ --H, 2 protons) and0.83 (triplet, J=8Hz, 6a-CH₂ CH₃, 3 protons) ppm.

Anal. calcd. for C₁₈ H₂₃ NO₂ : C, 75.75; H, 8.12; N, 4.91; Found: C,75.50; H, 7.88; N, 4.76.

EXAMPLE 19

The crude mixture of dienolether from Example 18 (20.38 g.) in 120 ml.of benzene was added to a stirred solution of 6 g. of sodium borohydridein 150 ml. of ethanol and 15 ml. of water at 0°. The reaction mixturewas stirred at 0° for 30 minutes then at room temperature for 1 hour.Water (200 ml.) was added along with 100 ml. of benzene. The organicphase was separated and the aqueous phase was extracted three times withbenzene. Each organic extract was washed twice with saturated brine,then combined, dried, filtered and concentrated at reduced pressuregiving 21.7 g. of yellow-orange 3-(3-cycanopropyl)-6a-ethyl-1,2,3,a,7,8-octahydrocyclopenta[f][1]benzopyran-7β-ol. TLC analysisshowed a single spot, R_(f) 0.48 and no starting ketone. ir: ν_(max)^(film) 3450 (OH), 2250 (C.tbd.N) and 1650 (dienolether) cm⁻¹.

EXAMPLE 20

The dienolether from Example 19 (21.7 g.) in 500 ml. of toluene washydrogenated over 4 g. of AK-4 5% palladium on carbon at roomtemperature and 1 atmosphere for 6 hours. A total of 1725 ml. ofhydrogen was absorbed during this period. The catalyst was filtered withsuction through celite and the filter cake was washed well with freshtoluene. The combined filtrate and washings were concentrated at reducedpressure giving 20.15 g. of yellow oily6a,9a-trans-3-(3-cyanopropyl)-6a-ethyl-1,2,3,5,6,6a,7,8,9,9a-dechydrocyclopenta[f][1]benzopyran-7β-ol.ir: ν_(max) ^(film) 3475 (OH), 2250 (C.tbd.N), 1680 (enolether) cm⁻¹ ;the band at 1650 cm⁻¹ due to the dienolether was absent.

EXAMPLE 21

The above crude enolether from Example 20 (20.15 g.) was dissolved in200 ml. of acetone containing 25 ml. of 1N aqueous sulphuric acid. Thesolution was stirred at room temperature for 1 hour after which time TLCanalysis showed the absence of starting material.

The reaction mixture which contained6a,9a-trans-3-(3-cyanopropyl)-6a-ethyl-perhydrocyclopenta[f][1]benzopyran-4a,7β-diolwas cooled to 0° -5° (ice-bath) while 80 ml. of Jones reagent was addeddropwise over 20 minutes. After stirring at room temperature for 3hours, the excess oxidizing agent was decomposed with sodium bisulfitesolution. Saturated brine (200 ml.) was added and the mixture wasextracted with benzene (3 × 200 ml.). Each benzene extract was washedwith saturated aqueous sodium bicarbonate solution (2 × 200 ml.) andbrine (2 × 200 ml.). The combined organic solution was dried, filteredand concentrated at reduced pressure giving 14.2 g. (66%) of red,3a,7a-trans-4-(3-oxo-6-cyano-1-hexyl)-3a,4,7,7a-tetrahydro-7a-ethyl-1,5(6H)-indandione.

ir: ν_(max) ^(film) 2250 (C.tbd.N), 1740 (cyclopentanone C═O), 1715(saturated aliphatic and cyclohexanone C═O) cm⁻¹ (no OH present).

EXAMPLE 22

A 6.0 g. sample of the crude triketone from Example 21 was dissolved in50 ml. of ethanol and 25 ml. of 0.1N methanolic potassium hydroxide thenstirred and heated under reflux for 1.5 hours. The methanol wasevaporated at reduced pressure and the residue was treated withsaturated brine (100 ml.) and extracted with benzene (3 × 200 ml.). Eachbenzene extract was washed with brine (2 × 100 ml.). The combinedorganic extracts were dried, filtered and concentrated at reducedpressure giving 5.3 g. of dark red, oily product. uv: λ_(max) ^(EtOH)246 Mμ(ε10300), 300 (915).

This material was chromatographed on 250 g. of silica gel. The fractionseluted with 4:1 and 2:1 benzene:ether which were homogeneous on TLCanalysis (R_(f) 0.4; strong uv spot) gave 2.55 g. of pale-yellow oil.The other fractions (1.10 g.) showed the presence of a slower movingimpurity, R_(f) 0.3 (˜ 70% desired material present).

One of the purer fractions was rechromatographed on silica gel givingtrans-anti-6-(2-cyanoethyl)-3a-ethyl-1,2,3a, 4,5,9,9a,9b-octahydro-3H-benz[e]inden-3,7(8H)-dione as a colorless oil with thefollowing physical properties:

ir: ν_(max) ^(CHCl).sbsp.3 2255 (C.tbd.N), 1740 (cyclopentanone C═O),1670 (α,β-unsaturated ketone C═O), 1600 (C═C) cm⁻¹ ; nmr: δ_(TMS)^(CDCl).sbsp.3 0.86 (triplet, J=8Hz, 3a--CH₂ CH₃, 3 protons) ppm. uv:λ_(max) ^(EtOH) 245/6 mμ(ε=12,600).

Anal. calcd. for C₁₈ H₂₃ N0₂ : C, 75.75; H, 8.12; N, 4.91; Found: C,75.79; H, 7.99; N, 4.91.

EXAMPLE 23

A 4.0 g. sample of the crude triketone from Example 21 was dissolved in200 ml. of toluene and 0.90 g. of p-toluenesulfonic acid monohydrate wasadded. The mixture was stirred and brought to reflux over 1 hour thenrefluxed with azeotropic removal of water (Dean-Stark trap) for 4 hours.After cooling to room temperature, the reaction mixture was washed withsaturated aqueous sodium bicarbonate (2 × 100 ml.), and saturated brine(1 × 100 ml.). The aqueous washings were back extracted with methylenechloride (3 × 100 ml.). The combined organic extracts were dried,filtered and concentrated at reduced pressure giving 3.5 g. of an orangesemi-solid residue.

This material was triturated under ethyl acetate and the solid wasfiltered off and washed well with ethyl acetate until nearly colorless.The combined filtrate and washings from the above purification wereconcentrated at reduced pressure and the residue was chromatographed on140 g. of silica gel. The fractions eluted with 4:1 and 2:1benzene:ether gave 0.95 g. (25.2%) of pale-yellow oil. The ir spectrumand TLC of this material were identical to that of enedione prepared inExample 22.

EXAMPLE 24

A 1.15 g. sample of enedione from Example 22 (purified bychromatography) was dissolved in 40 ml. of dry tetrahydrofurancontaining 1 ml. of triethylamine and hydrogenated over 0.2 g. of AK-4(5% palladium on carbon) at room temperature and one atmosphere for 2.5hours. The hydrogen uptake amounted to 121 ml. The catalyst was filteredwith suction through celite and the filtrate was concentrated at reducedpressure giving 1.14 g. of colorless oilytrans-anti-trans-anti-6-(2-cyanoethyl)-3a-ethyl-1,2,3a,4,5,5a,8,9,9a,9b-decahydrobenz[e]inden-3,7(6H)dione.TLC analysis showed a single spot R_(f) 0.4.

This material was chromatographed on 50 g. of silica gel. The fractionseluted with 9:1, 4:1 and 2:1 benzene:ether afforded 0.906 g. (78.5%) ofcolorless crystals. Recrystallization from 2-propanol gave theanalytical specimen as colorless crystals, m.p. 118.5°-121.0°.

ir: ν_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N), 1740 (cyclopentanone C═O),1715 (cyclohexanone C═O) cm⁻¹.

Anal. calcd. for C₁₈ H₂₅ NO₂ : C, 75.22; H, 8.77; N, 4.87; Found: C,75.40; H, 9.07; N, 4.87.

EXAMPLE 25

A pure sample of dione from Example 24 (0.2 g.) was dissolved in 5 ml.of dry tetrahydrofuran and treated with 0.5 ml. of ethylene glycol, 0.5ml. of trimethylorthoformate and 0.01 ml. of concentrated sulfuric acid.The resulting solution was stirred at room temperature for 5.5 hours. Atthe end of this time TLC analysis showed a single spot, R_(f) 0.48 andno starting material present. After addition of several drops oftriethylamine then 2 ml. of 10% aqueous sodium hydroxide, the mixturewas extracted three times with benzene. The combined organic extractswere washed twice with saturated brine, dried, filtered and concentratedat reduced pressure giving 0.264 g. (100%) of crudetrans-anti-trans-anti-3,3,7,7-bis(ethylenedioxy)-3a-ethyl-6(2-cyanoethyl)perhydro-1H-benz[e]indeneas a beige powder. Recrystallization from 2 propanol gave 0.214 g. ofcolorless crystals, m.p. 127.5°-129.5°.

ir: ν_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N), 1160, 1100, 1050 cm⁻¹ ; nmr:δ_(TMS) ^(CDCl).sbsp.3 3.96, 3.86 (singlets, 8 ethylene ketal protons)ppm.

Anal. calcd. for C₂₂ H₃₃ NO₄ : C, 70.37; H, 8.86; N, 3.73; Found: C,70.32; H, 8.56; N, 3.52.

EXAMPLE 26

A solution of 0.164 g. of pure diketal nitrile from Example 25 in 25 ml.of anhydrous ether was added dropwise from a syringe to a solution of 2ml. of ˜2M ethereal methyllithium in 5 ml. of anhydrous ether at -15°.The mixture was stirred at -10° for 1.75 hours then decomposed by theaddition of 2 ml. of water at 0°. After stirring at room temperature for1.5 hours, the mixture was extracted three times with ether and thecombined ether extracts were washed twice with saturated brine, dried,filtered and concentrated at reduced pressure. This gave 0.165 g. (97%)oftrans-anti-trans-anti-3,3,7,7-bis(ethylenedioxy)-3a-ethyl-6-(3-oxo-1-butyl)perhydro-1H-benz[e]indeneas a beige solid. TLC analysis showed a major spot, R_(f) 0.42 and atrace of a faster moving spot, the R_(f) of which corresponded to thatof the starting nitrile.

This material was recrystallized from 2-propanol giving 0.082 g. ofcolorless, fluffy crystals, m.p. 116°-119°.

ir: ν_(max) ^(CHCl).sbsp.3 1710 (ketone C═O), 1155, 1100, 1055 cm⁻¹ ;nmr: δ_(TMS) ^(CDCl).sbsp.3 3.88, 3.82 (singlets, 8 ethylene ketalprotons), 2.06 singlet, CH₃ --C--O, 3 protons) ppm.

EXAMPLE 27

A solution of 0.124 g. of diketal from Example 26 in 7 ml. of methanoland 2 ml. of 4N aqueous hydrochloric acid was refluxed for 4 hours.After cooling to room temperature, the reaction mixture was treated withsaturated brine and extracted three times with benzene. The combinedorganic extracts were washed once with saturated aqueous sodiumbicarbonate solution, once with brine, dried, filtered and concentratedat reduced pressure. This gave 0.110 g. of crude, yellow crystalline13β-ethylgon-4-en-3,17-dione which showed essentially one strongly UVfluorescent spot, R_(f) 0.4 on TLC analysis.

This material was chromatographed on 5 g. of silica gel. The fractionseluted with 2:1 and 1:1 benzene-ether gave 0.083 g. (92%) of pale-yellowcrystalline material. Recrystallization from methanol afforded 0.056 g.of pure product as colorless crystals, m.p. 156°-159°.

ir: ν_(max) ^(CHCl).sbsp.3 1735 (cyclopentanone C═O), 1670(α,β-unsaturated ketone (C═O), 1625 (C═C) cm⁻¹ ; uv: λ_(max) ^(EtOH) 230mμ(ε18000); nmr: δ_(TMS) ^(CDCl).sbsp.3 5.82 (singlet, C₄ -H, 1 proton),0.81 (triplet, --CH₂ CH₃, 3 protons) ppm.

EXAMPLE 28

A 16.7 g. (0.1 mole) sample of the lactone prepared in Example 3 wastreated with 76 ml. (0.16 mole) of 2.1M vinylmagnesium chloride solutionin THF using the procedure described in Example 4. After the samework-up, the THF extracts [containing6-(3-cyanopropyl)-2-vinyltetrahydropyran-2-ol] were then treated with12.1 g. of (-)-S-α-methylbenzylamine and left at room temperature for 3hours. The solvents were removed at reduced pressure and the residue wasdissolved in a mixture of 125 ml. of acetone and 125 ml. of 1.5N aqueoussulfuric acid solution. After 15 minutes at room temperature thismixture was extracted with 100 ml. of n-hexane and the hexane extractwas reextracted with 30 ml. of 1:1 acetone:1N aqueous sulphuric acid.

The combined acid aqueous extract was made alkaline with 10% aqueoussodium carbonate solution and the Mannich base(2-[2-(S-α-phenethylamino)ethyl]-6-(3-cyanopropyl)-tetrahydropyran-2-ol)was isolated by ether extraction of (1 × 100 ml.; 3 × 50 ml.). Thecombined ether solutions were washed with brine, dried and concentratedat reduced pressure giving 28.5 g. of residue.

This material was dissolved in 65 ml. of acetone and added to a solutionof 9.2 g. of oxalic acid in 65 ml. of acetone and left at roomtemperature for 24 hours. The solids were filtered with suction andwashed with 25 ml. of acetone and 60 ml. of 1:1 acetone:isopropyl ethermixture and dried under high vacuum over P₂ O₅. The white solid (10.5g., m.p. 107°-111° (Hot Stage), [α]_(D) -33.8°) was recrystallized from50 ml. of acetonitrile to yield 9.33 g. (46%) of pure 2S,6R2-[2-(S-α-phenethylamino)ethyl]-6-(3-cyanopropyl)-tetrahydropyran-2-oloxalate m.p. 108°-12° (Hot Stage), [α]_(D) -36.6° (C═2.26, CH₃ OH). Theanalytical specimen, obtained by several recrystallizations of a samplefrom acetone showed m.p. 108°-109° (capillary), [α]_(D) -35.28° (C=1.0,CH₃ OH).

Anal. calcd. for C₁₉ H₂₈ N₂ O₂ . C₂ H₂ O₄ : C, 62.05; H, 7.44; N, 6.89;Found: C, 62.37; H, 7.65; N, 6.84.

EXAMPLE 29

To a suspension of 6.1 g. of oxalate from Example 28 in 60 ml. of water,sodium carbonate was added until the mixture showed pH 9. The free basewas then extracted with several portions of ether.

The combined ether extracts were washed with brine, dried, filtered,concentrated at reduced pressure and dried under high vacuum giving 4.65g. of2S,6R,2-[2-(S-α-phenethylamine)ethyl]-6-(3-cyanopropyl)tetrahydropyran-2-olas a light yellow oil, [α]_(D) ²⁵ -20.39° (C=0.9759 in benzene). ir:ν_(max) ^(CHCl).sbsp.3 3100 (bonded OH, NH), 2250 (C.tbd.N) cm⁻¹.

Anal. calcd. for C₁₉ H₂₈ N₂ O₂ : C, 72.11; H, 8.92; N, 8.85; Found: C,72.17; H, 8.85; N, 9.05.

EXAMPLE 30

A mixture of 4.55 g. of the free base from Example 29 110 ml. ofmethanol, 0.460 g. of sodium bicarbonate and 2.0 g. of freshly distilledbenzaldehyde was stirred and heated at reflux for 8.5 hours. Thereaction mixture was then concentrated to a volume of 10 ml., dilutedwith saturated brine and extracted with methylene chloride. The combinedorganic extracts were washed with brine, dried, filtered andconcentrated at reduced pressure giving 6.4 g. of oily product. This waschromatographed on 65 g. of silica gel. Elution with ether, 4:1 and 2:1ether:ethyl acetate afforded 3.07 g. (92%) of pure 2S,6R,2-(2-methoxyethyl)-6-(3-cyanopropyl)tetrahydropyran-2-ol as an oil. ir:ν_(max) ^(film) 3470 (OH), 2250 (C.tbd.N), and 1720 (ketone C═O) cm⁻¹.

EXAMPLE 31

A mixture of 2.27 g. of methanol adduct from Example 30 1.35 g. of2-methylcyclopentan-1,3-dione, 40 ml. of toluene and 20 ml. of aceticacid was stirred and heated at 110° for 5 hours. The bath temperaturewas then raised to 140° for 1 hour, during which time azeotropicdistillation of water into a Dean-Stark trap was carried out. The cooledmixture was washed with saturated brine, saturated aqueous sodiumbicarbonate solution and again with brine. The aqueous washings werereextracted with benzene and the combined benzene solutions were dried.Filtration and solvent removal afforded 2.8 g. of a crude, crystallinemixture of 3S,6aS and 3S,6aR-3(3-cyanopropyl)-6a-methyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][1]benzopyran-7(8H)-onewhich was chromatographed on 250 g. of silica gel. The fractions elutedwith 19:1 benzene:ether furnished 2.02 g. of solid m.p. 72°-96°, [α]_(D) ²⁵ -150.86° (C=0.9207 in chloroform).

This material was recrystallized from 9 ml. of 2-propanol giving 1.02 g.(37.7%) of pure3S,6aS,3-(3-cyanopropyl)-6a-methyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][1]benzopyran-7(8H)-onem.p. 101°-104°, [α] _(D) ²⁵ -182.0° (C=1.0 in chloroform). A sample wasrecrystallized several times to afford an analytical sample m.p.102°-104°, [α] _(D) ²⁵ -184.42° (C=1.0335 in CHCl₃).

ir: ν_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N), 1740 (cyclopentanone C═O) and1640 (dienolether) cm⁻¹ ; uv: λ_(max) ^(EtOH) 254 mμ(ε18800); nmr:δ_(TMS) ^(CDCl).sbsp.3 5.41 (triplet, J=2Hz, H--C═, 1 proton); 3.78(multiplet, H--C--O, 1 proton), 1.10 (singlet, C_(3a) --CH₃, 3 protons)ppm.

Anal. calcd. for C₁₇ H₂₁ NO₂ : C, 75.24; H, 7.80; Found: C, 75.17; H,7.95.

EXAMPLE 32

A solution of 1.02 g. of dienolether from Example 31 in 6 ml. of ethanoland 5 ml. of benzene was added dropwise to a stirred solution of 0.25 g.of sodium borohydride in 5 ml. of water and 5 ml. of ethanol at 0°.After stirring at room temperature for 15 minutes, the reaction mixturewas poured into water and extracted with methylene chloride. Thecombined organic extracts were washed with brine, dried, filtered andconcentrated at reduced pressure affording 1.01 g. of3S,6aS,3-(3-cyanopropyl)-6a-methyl-1,2,3,5,6,6a,7,8-octahydrocyclopenta[f][1]benzopyran-7β-ol,m.p. 115°-120°, [α] _(D) ²⁵ -190.68° (C=0.9348 in chloroform). A samplewas recrystallized from 2-propanol at -15° to give an analytical sample,m.p. 116°-119°, [α] _(D) ²⁵ -194.57° (C=1.012 in CHCl₃).

ir: ν_(max) ^(CHCl).sbsp.3 3650 (OH), 2250 (C.tbd.N) and 1640(dienolether) cm⁻¹ ; uv: λ_(max).sup. EtOH 254 mμ(ε19300); nmr; δ_(TMS)^(CDCl).sbsp.3 5.01 (multiplet, H--C═, 1 proton), 3.93 (multiplet,H--C--OH), 3.73 (multiplet, H--C--O), 0.93 (singlet, C_(6a) --CH₃,3protons) ppm.

Anal. calcd. for C₁₇ H₂₃ NO₂ : C, 74.69; H, 8.48; Found: C, 74.55; H,8.61.

EXAMPLE 33

A solution of 0.75 g. of dienolether from Example 32 in 15 ml. of dryether and 5 ml. of dry tetrahydrofuran was added dropwise to 11 ml. of a2M ethereal methylmagnesium chloride solution with stirring, at 0°. Thereaction mixture was stirred at 0° for 1 hour and at room temperaturefor 4 hours, then poured into saturated aqueous ammonium chloridesolution and extracted with ether. The combined ether extracts werewashed with brine and dried. Filtration and solvent removal gave 0.569g. of crude product which was chromatographed on 30 g. of silica gel.The fractions eluted with 2:1 and 1:1 benzene:ether and ether aloneafforded pure, crystalline3S,6aS-3-(4-oxo-1-pentyl)-6a-methyl-1,2,3,5,6,6a,7,8-octahydrocyclopenta[f][1]benzopyran-7β-ol(0.151 g.), [α] _(D) ²⁵ -165.17° (C=0.689 in CHCl₃).

ir: ν_(max) ^(CHCl).sbsp.3 3620 (OH) 1720 (ketone C═O) and 1640(dienolether) cm⁻¹ ; uv: λ_(max) ^(EtOH) 254 mμ(ε18320).

EXAMPLE 34

A mixture of 130.5 mg. of dienolether from Example 33, 15 ml. of xyleneand 1.3 g. of silver carbonate-celite reagent was stirred and heatedunder reflux for 1 hour. After cooling, the solids were filtered off andwashed several times with benzene. The filtrate was evaporated atreduced pressure to give 100 mg. of crude product which waschromatographed on 20 g. of silica gel. Elution with 19:1 and 4:1benzene:ether gave 60 mg. of3S,6aS,3-(4-oxo-1-pentyl)-6a-methyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][1]benzopyran-7(8H)-one m.p. 67°-70°, [α] _(D) ²⁵ -157.95° (C=0.9883 inCHCl₃). This material was recrystallized from aqueous methanol to give apure sample m.p. 72.5°-74°, [α] _(D) ²⁵ -163.90 (C=1.0427 in CHCl₃);

ir: ν_(max) ^(CHCl).sbsp.3 1740 (cyclopentanone C═O), 1710 (ketone C═O)and 1640 (dienolether) cm⁻¹ ; uv: λ_(max) ^(EtOH) 253 mμ(ε19000).

EXAMPLE 35

A solution of methanol adduct from Example 30 (605 mg.) in methanol (6.0ml.) and trimethylorthoformate (0.9 ml.) was treated withborontrifluoride etherate (60 mg.) After the resulting mixture wasstirred at room temperature for 15 minutes, it was treated with anadditional 30 mg. of borontrifluoride etherate and stirred for another15 minutes at room temperature. The mixture was then poured into excesssodium bicarbonate solution and the resulting mixture was extracted withether three times. The combined ether extract was washed with brine andthen dried. Filtration and solvent removal afforded crude2S,6R-2-methoxy-2-(2-methoxyethyl)-6-(3-cyanopropyl)-tetrahydropyran(590 mg.) as an oil. ir: ν_(max) ^(film) 2250 (C.tbd.N) cm⁻¹. Theabsence of hydroxyl and ketone in the ir indicated that the reaction wascomplete. Chromatography on silica gel and elution with benzene:ether9:1 and 4:1 afforded a pure sample [α] _(D) ²⁵ -72.97° (C=1.1238 inchloroform) or [α] _(D) ²⁵ -63.46° (C=1.0385 in benzene); ir: ν_(max)^(CHCl).sbsp.3 2250 (C.tbd.N) cm⁻¹ ; nmr; δ_(TMS) ^(CDCl).sbsp.3 3.30,3.15 (singlets, 6 methoxy protons) ppm.

Anal. Calcd. for C₁₃ H₂₃ NO₃ : C, 64.69; H, 9.61; N, 5.80; Found: C,64.82; H, 9.76; N, 5.58.

EXAMPLE 36

An ethereal methyllithium solution (11 ml.; 2M) was cooled to -15° andstirred while a solution of the product from Example 35 (1.25 g.) inether (35 ml.) was added over a 10 minute period. After the resultingmixture was stirred for 30 minutes at -10° an aliquot was removed andtracted with excess saturated aqueous bicarbonate solution. The TLCanalysis showed essentially one spot (R_(f) 0.35) plus some minor polarspots (R_(f) 0.15 and 0.05). The absence of starting material (R_(f)0.4) indicated that the reaction was complete. The reaction mixture wasthen allowed to warm up to -5° C. and was treated with excess saturatedbicarbonate solution. The resulting mixture was stirred at roomtemperature for 1 hour. The aqueous layer was then separated andextracted three times with ether. The combined ether layers were washedwith brine and dried. Filtration and solvent removal afforded crude2S,6S-2-methoxy-2-(2-methoxyethyl)6-(4-oxo-1-pentyl)-tetrahydropyran(1.24 g.) as an oil. Chromatography on silica gel and elution withbenzene-ether 1:1 afforded a pure sample as a colorless oil. [α] _(D) ²⁵-66.55° (C=1.0684 in chloroform) or [α] _(D) ²⁵ -63.47° (C=1.010 inbenzene);

ir: ν_(max) ^(CHCl).sbsp.3 1710 (ketone C═O) cm⁻¹ ; nmr: δ_(TMS)^(CDCl).sbsp.3 3.31, 3.16 (singlets 6 methoxy protons) 2.13 (singlet,CH₃ CO, 3 protons) ppm.

Anal. calcd. for C₁₄ H₂₆ O₄ : C, 65.08; H, 10.14; Found: C, 65.10; H,10.08.

EXAMPLE 37

A mixture of ketoketal from Example 36 (948 mg.), toluene (19 ml.),2-methylcyclopentane-1,3-dione (620 mg.) and acetic acid (9 ml.) washeated to 115° C in an apparatus which was fitted with a Dean-Starktrap. The reaction mixture was stirred at this temperature for 15 hours.(slight reflux but not enough for distillation into the Dean-Starktrap). The temperature was then raised to 140° for 1 hour. The cooledmixture was washed with water, saturated sodium bicarbonate solution andbrine. The aqueous layers were reextracted with benzene and the combinedbenzene extracts were washed again with brine. Drying and solventremoval afforded crude crystalline3S,6aS,3-(4-oxo-1-pentyl)-6a-methyl-1,2,3,5,6a-hexahydrocyclopenta[f][1]benzopyran-7(8H)-one(1.02 g.). This material was dissolved in methanol (7 ml.) and slowlytreated with water (3 ml.) over a period of 15 minutes. A first crop(421.6 mg.) was obtained, m.p 67.5°-72° C., [α] _(D) ²⁵ -157.5° (C=1.01in chloroform). The mother liquor from the crystallization was treatedwith more water (1.5 ml.) over a period of 1 hour. In this way a secondcrop (246.1 mg.) was obtained, m.p. 61°-67° C., [α] _(D) ²⁵ -147.7°(C=1.13 in chloroform). The first and second crops were recrystallizedtogether from aqueous methanol to afford a pure sample (528.4 mg.; 50%);m.p. 71°-74° C; [α] _(D) ²⁵ -163.65° (C=0.9331 in chloroform);

ir: ν_(max) ^(CHCl).sbsp.3 1740 (cyclopentanone C═O), 1710 (ketone C═O),1640 (dienolether) cm⁻¹ ; uv: λ_(max) ^(EtOH) 254 mμ(ε18600).

EXAMPLE 38

A solution of dienolether from Example 32 (5.8 g.; crude reductionproduct) in toluene (30 ml.) and tetrahydrofuran (20 ml. dried overaluminum oxide grade I) was hydrogenated under one atmosphere and roomtemperature using a 5% palladium on carbon catalyst (1.0 g., AK-4). Theuptake (500 ml.) of hydrogen stopped after about 2 hours. The catalystwas filtered off and washed with THF. Solvent removal gave crude3S,6aS,6a,9a-trans-3-(3-cyanopropyl)-6a-methyl-1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f][1]benzopyran-7β-olas an oil (5.66 g.). The ir spectrum showed absorptions 1680 cm⁻¹(enolether), 2250 cm⁻¹ (nitrile) and 3620 cm¹ (hydroxy). This crudeproduct was used for the next step.

EXAMPLE 39

A mixture of crude enolether from Example 38 (5.66 g.), acetone (110ml.) and 1N sulfuric acid (30 ml.) was allowed to stand at roomtemperature for 1 hour. The reaction mixture containing3S,6aS,6a,9a-trans-3-(3-cyanopropyl)-6a-methylperhydrocyclopenta[f][1]benzopyran-4a,7β-diolwas then stirred and cooled to 0° and treated with freshly preparedJones Reagent (21.5 ml.) over a period of 15 minutes. After addition,the mixture was stirred at room temperature for 3 hours. Under cooling,sodium bisulfite was added until the color of the solution turned green.The mixture was diluted with saturated brine and then extracted withbenzene several times. The benzene layers were washed with saturatedsodium bicarbonate and brine and then dried. Filtration and solventremoval afforded crude6aS-trans-anti-4-(3-oxo-6-cyano-1-hexyl)3a,4,7,7a-tetrahydro-7aβ-methyl-1,5(6H)-indandioneas an oil. This crude product was used in the next stp withoutpurification.

EXAMPLE 40

A mixture of triketone from Example 39 (4.6 g., crude), toluene (200ml.) and p-toluene sulfonic acid monohydrate (1.0 g.) was stirred andrefluxed, under nitrogen, using a Dean-Stark trap for 4.5 hours aftervigorous refluxing began. The cooled solution was washed twice withsaturated sodium bicarbonate solution. The aqueous layers were backextracted with methylene chloride and the combined organic solutionswere dried. Filtration and solvent removal afforded a semi-solid residue(4.0 g.). This material was triturated under ethyl acetate and the solidwas suction filtered and washed with ethyl acetate. The combinedfiltrate and washings were concentrated and the residue (3.3 g.)chromatographed on silica gel (300 g.). Elution withbenzene:ethylacetate 2:1 and 1:1 afforded 1.93 g. oil, TLC one spot. A1.1 g. sample of this material was rechromatographed on silica gel (100g.). Elution with benzene:ethylacetate 4:1 and 2:1 afforded(+)-trans-anti-6(2-cyanoethyl)-3aβ-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e]inden-3,7(8H)-dione(541.9 mg., semicrystalline). This material was triturated with etherand a little benzene to afforded a pure sample (392.4 mg.) as colorlesssolid m.p. 111°-117° C., [α] _(D) ²⁵ +52.5° (C=1.0 in chloroform).Recrystallization from 2-propanol afforded a pure analytical sample(308.6 mg.) m.p. 116°-119° C., [α] _(D) ²⁵ +53.9° (C=0.9073 inchloroform). ir: ν_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N), 1740(cyclopentanone C═O), 1665 (α,β-unsaturated ketone C═O), 1605 (C═C) cm⁻¹; uv: λ_(max) ^(EtOH) 245 (ε13400)mμ; nmr: δ_(TMS) ^(CDCl).sbsp.3 1.04(singlet, C₁₃ --CH₃) ppm.

Anal. calcd. for C₁₇ H₂₁ NO₂ : C, 75.24; H, 7.80; N, 5.16; Found: C,74.98; H, 7.71; N, 5.00.

EXAMPLE 41

A 12.2 g. sample of triketone from Example 39 was dissolved in 40 ml. ofmethanol and treated with 43 ml. of a methanolic potassium hydroxidesolution (0.0132 g./ml.). After heating at reflux for 45 minutes, thereaction mixture was cooled, diluted with saturated brine and theorganic materials were extracted with methylene chloride. The combinedorganic extracts were dried, filtered and concentrated at reducedpressure. Recrystallization of the residue from 2-propanol gave 6.3 g.of pure (+)-trans-anti-6-(2-cyanoethyl)-3aβ-methyl-1,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e]inden-3,7(8H)-dione, m.p.115°-117°. [α] _(D) ²⁵ +55.1° (C=1.5002; CHCl₃) uv: λ_(max) ^(EtOH) 243mμ(ε14000); ir: ν_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N), 1735(cyclopentanone C═O), 1665 (cyclohexenone C═O) and 1603 (C═C) cm⁻¹.

Anal. calcd. for C₁₇ H₂₁ NO₂ : C, 75.25; H, 7.80; N, 5.16; Found: C,74.98; H, 7.71; N, 5.00.

EXAMPLE 42

A solution of enedione from Example 41 (230 mg.) in dry tetrahydrofuran(8 ml.) and triethylamine (0.23 ml.) was stirred in an atmosphere ofhydrogen over 5% palladium on carbon (46 mg., AK-4). After 2 hours, 30ml. of hydrogen was absorbed (19 ml. theory). The hydrogenation wasstopped, the catalyst was filtered off and washed with benzene and thecombined filtrate and washings concentrated to give crude,semi-crystalline product (228 mg.). This product was triturated with2-propanol (2 ml.) to afford(+)-trans-anti-trans-anti-6-(2-cyanoethyl)-3aβ-methyl-1,2,3a,4,5,5a,8,9,9a,9b-decahydrobenz[e]inden-3,7-(6H)-dione(190 mg.) as a white solid, m.p. 129°-134°. An analytical specimen wasobtained by recrystallization from 2-propanol, m.p. 135°-136°, [α] _(D)²⁵ +78.91° (C=1.0354 in CHCl₃); ir: ν_(max) ^(CHCl).sbsp.3 2250(C.tbd.N), 1740 (cyclopentanone C═ O), 1710 (cyclohexanone C═O) cm⁻¹ ;nmr: δ_(TMS) ^(CDCl).sbsp.3 0.97 (singlet, C_(3a) --CH₃) ppm.

Anal. calcd. for C₁₇ H₂₃ NO₂ : C, 74.69; H, 8.48; N, 5.12; Found: C,74.60; H, 8.79; N, 5.13.

EXAMPLE 43

A solution of diketone from Example 42 (200 mg.), methanol (2 ml.)trimethylorthoformate (0.45 ml.) and borontrifluoride etherate (0.03ml.) was stirred for 15 minutes at room temperature and then poured intoexcess saturated aqueous sodium bicarbonate solution and extracted threetimes with benzene. The combined benzene extracts were washed with brineand then dried. Filtration and solvent removal afforded a crude oil (242mg.). The ir of this sample still showed absorptions at 1740 and 1720cm⁻¹ (cyclopentanone and cyclohexanone; approximately 30% startingmaterial left).

A solution of the sample above (242 mg.) in methanol (2.0 ml.),trimethylorthoformate (0.5 ml.) and 70% aqueous perchloric acid (0.02ml.) was stirred at room temperature for 30 minutes. The reactionmixture was cooled to 0°-5° C. and treated first with triethylamine(0.03 ml.) and then with sodium bicarbonate (100 mg.). The mixture waspoured into excess saturated aqueous sodium bicarbonate solution andextracted three times with benzene. The combined benzene extracts werewashed with brine and then dried. Filtration and solvent removalafforded a crude oily mixture oftrans-anti-trans-anti-3,3,7,7-tetramethoxy-3aβ-methyl-6-(2-cyanoethyl)perhydro-1H-benz[e]indeneand an enol ether at the 6,7- or 7,8-position (241.1 mg.). ir: ν_(max)^(film) 2840 (OCH₃), 2250 (C.tbd.N), weak bands at 1740 (cyclopentanoneC═O), and 1670 (enolether) cm⁻¹.

EXAMPLE 44

A solution of crude product from Example 43 (240 mg.) in anhydrous ether(15 ml.) was stirred with cooling in an ice-salt bath at -15° to 0°,while 2M ethereal methyllithium (1.5 ml., 3 mole) was quickly added froma syringe. The resulting mixture was stirred at -10° to 0° for 1.5hours, then treated with excess saturated aqueous ammonium chloridesolution. The ether layer was separated and the aqueous phase wasextracted twice with ether. The combined ether solutions were washedwith brine and then dried. Filtration and solvent removal afforded amixture oftrans-anti-trans-anti-3,3,7,6-tetramethoxy-3aβ-methyl-6-(3-oxo-1-butyl)perhydro-1H-benz[e]indene and the corresponding enol ether (194.8 mg.).ir: ν_(max) ^(film) 2840 (OCH₃), 1740 and 1720 (C═O, partial hydrolysisof ketals) and 1670 (enolether) cm⁻¹. The absence of nitrile at 2250cm⁻¹ indicated that the reaction was complete.

EXAMPLE 45

A solution of diketone from Example 42 (190.0 mg.) in drytetrahydrofuran (5.0 ml.) was treated with ethylene glycol (0.4 ml.),trimethylorthoformate (0.4 ml.) and concentrated sulfuric acid (0.02ml.). The resulting solution was stirred at room temperature for 1.5hours and then treated first with triethylamine (0.04 ml.) and then with10% aqueous sodium hydroxide solution (2.0 ml.). The resulting mixturewas extracted with benzene three times. The combined benzene layers werewashed with brine and then dried. Filtration and solvent removalafforded (253 mg.) of a crude solid. This material was recrystallizedtwice from 2-propanol to afford pure(+)-trans-anti-trans-anti-3,3,7,7-bis(ethylenedioxy)-3aβ-methyl-6-(2-cyanoethyl)perhydro-1H-benz[e]indene(169 mg.), m.p. 130°-131° C., [α]_(D) ²⁵ +0.67° (C=1.0363 in CHCl₃). ir:ν_(max) ^(CHCl).sbsp.3 2250 (C.tbd.N) cm⁻¹ ; nmr: δ_(TMS) ^(CDCl).sbsp.33.96, 3.86 (singlets, 8 ethylene ketal protons), 0.88 (singlet, C_(3a)-CH₃) ppm.

Anal. calcd. for C₂₁ H₃₁ NO₄ : C, 69.77; H, 8.65; N, 3.88; Found: C,69.93; H, 8.50; N, 3.91.

EXAMPLE 46

An ethereal methyllithium solution (2.0 ml. 2M) was cooled to -15° andstirred while a solution of nitrile bis-ketal from Example 45 (176.0mg.) in anhydrous ether (10 ml.) was added over a 5 minute period. Thereaction mixture was stirred at -15° to 0° for 30 minutes and thentreated at 0° with water (3.0 ml.). After dilution with brine, the etherlayer was separated and the aqueous layer was extracted twice withether. The combied ether layers were washed with brine and then dried.Filtration and solvent removal afforded the crude product (185.2 mg.) asan oil. This material was chromatographed on silica gel (18 g.). Elutionwith benzene:ether 2:1 and 1:1 afforded pure(-)-trans-anti-trans-anti-3,3,7,7-bis-(ethylenedioxy)3aβ-methyl-6-(3-oxo-1-butyl)perhydro-1H-benz[e]indene(151.5 mg., 82.5%) as a colorless solid, m.p. 77°-81° C., [α]_(D) ²⁵-6.2° (C=1.0 CHCl₃). ir: ν_(max) ^(CHCl).sbsp.3 1720 (ketone C═O) cm⁻¹.

EXAMPLE 47

A solution of the mixture from Example 44 (194 mg.) in methanol (5 ml.)and 4N aqueous hydrochloric acid solution (1.5 ml.) was stirred andrefluxed for 4 hours. After cooling, the reaction mixture was dilutedwith brine and extracted with benzene three times. The combined benzenelayers were washed with brine and then dried. Filtration and solventremoval afforded crude product (136.2 mg.). This material waschromatographed on silica gel (7.5 g.). Elution withbenzene:ethylacetate 9:1 and 4:1 affordedd-(+)-19-norandrost-4-en-3,17-dione (110.1 mg.), m.p. 166°-170°, [α]_(D)²⁵ +131.0° (C=0.50 CHCl₃). Recrystallization from aqueous methanol gavea pure sample (54.7 mg.) as colorless needles, m.p. 170.5°-172°, [α]_(D)²⁵ +141.55° (C=1.0703 in chloroform). ir: ν_(max) ^(CHCl).sbsp.3 1740(cyclopentanone C═O), 1665 (enone C═O), 1620 (C═C) cm⁻¹ uv: λ_(max)^(EtOH) 239 mμ(ε17400).

Anal. calcd. for C₁₈ H₂₄ O₂ : C, 79.37; H, 8.88; Found: C, 79.41; H,9.09.

EXAMPLE 48

A solution of keto bis-ketal from Example 46 (151.5 mg.) in methanol(4.5 ml.) and 4N aqueous hydrochloric acid solution (1.5 ml.) wasstirred and refluxed for 4 hours. After cooling, the reaction mixturewas diluted with brine and extracted with benzene three times. Thecombined benzene layers were washed with brine and then dried.Filtration and solvent removal afforded crude product (92.6 mg.) as asolid. Recrystallization from aqueous methanol gave pured-(+)-19-norandrost-4-en-3,17-dione (57.0 mg.) as a colorless needles,m.p. 169°-172° C.; mixed m.p. with an authentic sample 169°-171° C.;[α]_(D) ²⁵ +139.15° (C=1.0492 in chloroform); ir: ν_(max) ^(CHCl).sbsp.31740 (cyclopentanone C═O), 1665 (enone C═O), 1620 (C═C) cm⁻¹ ; uv:λ_(max) ^(EtOH) 240 mμ(ε17720).

EXAMPLE 49

A solution of 0.5 g. (1.845 moles) of the dienol ether from Example 5 in15 ml. of dry ether and 7 ml. of dry tetrahydrofuran was stirred withcooling at 0° while 12.5 ml. (4.61 mole equivalent) of 0.369 M etherealmethylmagnesium chloride was added dropwise over 5 minutes. Theresulting slurry was stirred at 0° for 1.5 hours, then treated with 5ml. of saturated ammonium chloride, diluted with brine and extractedthree times with ether. The ether extracts were combined, washed withbrine, dried, filtered and concentrated at reduced pressure giving 0.58g. of oily3-(3-cyanopropyl)-6aβ,7α-dimethyl-1,2,3,5,6,6a,7,8-octahydrocyclopenta[f][1]benzopyran-7β-ol.ir: ν_(max) ^(film) 3456 (OH), 2250 (C.tbd.N), 1750 (trace-startingcyclopentanone), 1645 (dienolether) cm⁻¹. TLC analysis showed a newmajor spot of slower R_(f) than the starting material as well as a traceof starting material.

The above compound may be converted to 17α-methyl-19-nor-testosterone,by proceeding in a manner similar to that described in Examples 7, 8, 9,11, 14, 15 and 17 via the intermediates6a,9a-trans-3-(3-cyanopropyl)-6aβ,7α-dimethyl-1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f][1]benzopyran-7β-ol,6a,9a-trans-3-(3-cyanopropyl)-6aβ,7α-dimethyl-perhydrocyclopenta[f][1]benzopyran-4a,7β-diol,3a,7a-trans-4-(3-oxo-6-cyano-1-hexyl)-3a,4,7,7a-tetrahydro-1α,7a.beta.-dimethyl-6H-indan-5-one,trans-anti-6-(2-cyanoethyl)-3α,3aβ-dimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydrobenz[e]inden-7-one,trans-anti-trans-anti-6-(2-cyanoethyl)-3α,3aβ-dimethyl-perhydrobenz[e]inden-3-one,trans-anti-trans-anti-7,7-ethylenedioxy-3α,3aβ-dimethyl-6-(2-cyanoethyl)perhydro-benz[e]-inden-3β-ol,andtrans-anti-trans-anti-7,7-ethylenedioxy-3α,3aβ-dimethyl-6-(2-cyanoethyl)-perhydrobenz[e]inden-3β-ol.

We claim:
 1. A compound of the formula ##STR22## where R₁₆ is di(lower)alkylamino mineral, non-optically active hydrocarbyl monocarboxylic ornon-optically active hydrocarbyl dicarboxylic acid addition salt ordesoxyephedrine mineral, non-optically active hydrocarbyl monocarboxylicor non-optically active hydrocarbyl dicarboxylic acid addition salt. 2.The compound of claim 1 wherein R₁₆ is an optically active aminemineral, non-optically active hydrocarbyl monocarboxylic ornon-optically active hydrocarbyl dicarboxylic acid addition salt.
 3. Thecompound of claim 1 which is2-(2-diethylaminoethyl)-6-(3-cyanopropyl)-tetrahydropyran-2-ol mineral,non-optically active hydrocarbyl monocarboxylic or non-optically activehydrocarbyl dicarboxylic acid addition salt.
 4. The compund of claim 3which is 2-(2-diethylaminoethyl)-6-(3-cyanopropyl)-tetrahydropyran-2-oloxalate.
 5. The compound of claim 2 wherein R₁₆ is desoxyephedrineoxalate.